Prabu Manoharan - Academia.edu (original) (raw)
Papers by Prabu Manoharan
Journal of Molecular Graphics and Modelling, 2018
The organophosphorus hydrolase enzyme is involved in the catalyzing reaction that involve hydroly... more The organophosphorus hydrolase enzyme is involved in the catalyzing reaction that involve hydrolysis of organophosphate toxic compounds. An enzyme from Deinococcus radiodurans reported as homologous to phosphotriesterase and show activity against organophosphate. In the past activity of this enzyme is low and efforts made to improve the activity by experimental mutation study. However only very few organophosphates tested against very few catalytic site mutations. In order to improve the catalytic power of the organophosphorus hydrolase enzyme, we carried out systematic functional hotspot based protein engineering strategy. The mutants tested against 46 know organophosphate compounds using molecular docking study. Finally, we carried out an extensive molecular docking study to predict the binding of 46 organophosphate compounds to wild-type protein and mutant organophosphorus hydrolase enzyme. At the end we are able to improve the degrading potential of organophosphorus hydrolase enzyme against organophosphate toxic compounds. This preliminary study and the outcome would be useful guide for the experimental scientist involved in the bioremediation of toxic organophosphate compounds.
Bioinformation, 2018
Geminiviridae is a large family of circular, single stranded DNA viruses, which infects and cause... more Geminiviridae is a large family of circular, single stranded DNA viruses, which infects and causes devastating diseases on economically important crops. They are subdivided into nine genera. Members of the genus begomovirus encode a pathogenic protein called AC2/C2whichinteracts that inactivates many plant proteins and trans-activates a number of host genes via the C-terminal transactivation domain. Hence, a sequence analysis on C-terminal region of AC2/C2 was completed. Analysis of 124 bipartite and 463 mono partite begomo viral AC2/C2 proteins revealed major differences in protein length, composition and position of acidic, aromatic and hydrophobic residues. Secondary structure analysis of AC2/C2 revealed the possible formation of C-terminal α-helix, which is similar to the acidic activation domain of many transcriptional activator proteins. Previous studies demonstrated that AC2 utilizes conserved late element (CLE) for the transactivation of viral genes and genome-wide mapping of same consensus in A. thaliana yielded 122 promoters with exact CLE consensus sequence. Analysis of protein interaction network for 106 CLE containing genes, 87 AC2 trans activated genes and 10 AC2 interacting proteins revealed a possible regulation of hundreds of host proteins which helps begomoviruses to produce a successful viral infection.
The divergence in catalytic actions of N-acetyl neuraminic lyase (NAL) superfamily proteins, all ... more The divergence in catalytic actions of N-acetyl neuraminic lyase (NAL) superfamily proteins, all of which have pyruvate as a substrate, suggests common ancestry. Lack of catalytic triad residues essential for binding pyruvate in annotated DHDPS proteins from Gram+ve B.clausii (PDBid-3E96) and O.hiyensis (PDBid-3D0C) indicated that these proteins are inactive and therefore could be possible early ancestors. Analysis revealed that the most appropriate cavity of these proteins is voluminous and has an elongated topography compared to the trimmed side-wise tilted cavity topography in all other NAL superfamily proteins. Strength and the morphology of the interface regions contouring the cavity are the significant determinants of the topography. It is possible that evolutionary forces led to modulation of the structural segments following the beta strand 5 and alpha helix 10, which are significant participants of interfacial regions. Major structural motions captured by molecular dynamics...
Bioorganic & Medicinal Chemistry Letters, 2017
Hitherto this is the first report pertaining to production of biofilm inhibitory compound(s) (BIC... more Hitherto this is the first report pertaining to production of biofilm inhibitory compound(s) (BIC) from Bacillus subtilis BR4 against Pseudomonas aeruginosa (ATCC 27853) coupled with production optimization. In order to achieve this, combinations of media components were formulated by employing statistical tools such as Plackett-Burman analysis and central composite rotatable design. It was evident that at 35 ml L-1 glycerol and 3.8 g L-1 casamino acid, anti-biofilm activity and production of extracellular protein significantly increased by 1.5-fold and 1.2-fold, respectively. These results corroborate that the combination of glycerol and casamino acid plays a key role in the production of BIC. Further, metabolic profiling of BIC was carried out using liquid chromatography/tandem mass spectrometry (LC-MS/MS) based on m/z value. The presence of Stigmatellin Y was predicted with monoisotopic neutral mass of 484.2825 Da. In support of optimization study, higher production of BIC was confirmed in the optimized-media-grown BR4 (OPT-BR4) than in the ideal-media-grown BR4 (ID-BR4) by LC-MS/MS analysis. PqsR in P. aeruginosa is a potential target for anti-virulent therapy. Molecular docking study has revealed that Stigmatellin Y interacts with PqsR in the similar orientation like a cognate signal (PQS) and synthetic inhibitor. In addition, Stigmatellin Y was found to exhibit interaction with four more amino acid residues of PqsR to establish strong affinity. Stigmatellin Y thus might play a role of competitor for PQS to distract PQS-PqsR mediated communication in P. aeruginosa. The present investigation thus paves new avenues to develop anti-Pseudomonas virulent therapy.
Journal of biomolecular structure & dynamics, Jan 12, 2017
More than 100 years of research on Alzheimer's disease didn't yield a potential cure for ... more More than 100 years of research on Alzheimer's disease didn't yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P-glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable. Identification and understanding of protein-ligand interactions are essential for ligand optimization process. Structure-based drug design (SBDD) efforts led to a steady accumulation of BACE1-ligand crystal complexes in the PDB. This study focuses on analyses of 153 BACE1-ligand complexes for the direct contacts (hydrogen bonds and weak interactions) observed between protein and ligand and indirect contacts (water-mediated hydrogen bonds), observed in BACE1-ligand complex crystal structures. Intraligand hydrogen bonds were analyzed, with focus...
Journal of Biomolecular Structure and Dynamics, 2016
The β-strand forming outer membrane proteins (OMPs) are found in the outer membrane of the Gram n... more The β-strand forming outer membrane proteins (OMPs) are found in the outer membrane of the Gram negative bacteria, eukaryotic organelles of prokaryotic origin, mitochondria, and chloroplasts. The OMPs present in the outer membrane plays a vital role in the maintenance of cell homeostasis. Two classes of OMPs were recognized within the outer membrane, one is peripheral and another is integral membrane proteins with unique β-barrel fold architecture. In Gram negative bacteria, OMPs are classified into six families based on the function (Koebnik, Locher, & Van Gelder, 2000). There are general porins (OMPC, OMPF, and PhoE), passive transporters (LamB, ScrY, FadL, and TodX), active transporters (siderophores transporters FepA, FecA, Fhu A, and vitamin B12 transporters BtuB), enzymes (phospholipase OmpLA or protease OmpT), defensive proteins (OmpX), and structural proteins (OmpA). Understanding the structure and function of OMPs is of critical importance, in the antibiotic design and development. In an antibacterial therapy, one of the main steps for the antibiotic is to cross the outer membrane through OMPs like OMPF present in S. typhi (Balasubramaniam, Arockiasamy, Kumar, Sharma, & Krishnaswamy, 2012). Most of the antibiotic targets are present within the bacterial cell; the antibiotics are known to take two routes to reach the targets. The hydrophobic antibiotics pass through the lipid and the hydrophilic molecules translocate through water-filled porins. The lipid and protein compositions of the outer membrane have a strong impact on the permeability of antibiotics and drug resistance. So, studies conducted on physico-chemical properties of amino acid residues along the pores and by considering the lipid–OMP interactions may provide valuable insights into the antibiotic resistance. Liposomeswelling assay is used to qualitatively characterize antibiotic translocation through porin. Later quantitative electrophysiology measurements were used. The OMPmediated antibiotic permeability is still not clearly understood. The availability of high resolution porin structure and further investigation on this reveals that antibiotic translocates by interacting with the surface of the channel. Ampicillin-binding site in the channel of OMPF is identified. Facilitated diffusion through a binding site was observed in maltoporin (Danelon, Brando, & Winterhalter, 2003). Computational molecular dynamics (MD) studies in the past have shed light on the antibiotic translocation process (Kumar et al., 2010). Moreover, the alteration or modification of porin expression is associated with antimicrobial resistance. The emergence of porin-related antibiotic resistance is a challenge for designing better antibiotics (Beceiro, Tomas, & Bou, 2013; Nikaido, 2003). There are limited studies on relating computational modeling/dynamics with experiments. A search on pubmed results in only 150 hits in which very few are interesting. An interesting work by Kumar et al., demonstrates the structural and dynamical properties of the two major porins (OmpF and OmpC) in Escherichia coli, using MD simulations and showed the relationship between pore amino acid properties and antibiotic transport (Kumar, Hajjar, Ruggerone, & Ceccarelli, 2010). They presented the results of transport properties using accelerated MD simulations to probe the diffusion of norfloxacin (a fluoroquinolone antibiotic) through the two porins OmpF/OmpC. Porins perform various functions by depending upon channels, regulation of porin expression and its structure. Although OMPs are commonly made of β-strands, it is interesting to observe the variety of completely different functions, that is been performed such as diffusion pores, substrate-specific transporters, signal transduction, and enzymatic activity. The transport of various substances
Molecular diversity, 2012
γ-Secretase (Gamma Secretase) is a potential drug target in Alzheimer's disease therapeutics.... more γ-Secretase (Gamma Secretase) is a potential drug target in Alzheimer's disease therapeutics. A sequel lead design study was undertaken on a series of bicyclononanes with an aim of identifying potent isofunctional chemotypes. Fragment-based bioisosteric replacement, which considers shape, chemistry, and electrostatics was carried out to mine over four million medicinally relevant fragments of Brood database. The resulting subset, thus, obtained was further mined using consensus QSAR developed from 2D and CoMFA, CoMSIA, GRIND (3D) QSAR predicted endpoints with superior statistical results. The employed consensus prediction and the predicted endpoint values were found to be in good agreement with the experimental values. The predictive ability of the generated model was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. Few analogs designed, using the concept of bioisosterism, were found to be...
Bioinformation, 2015
The viral envelope glycoproteins are essential for entry into their host cells and studied extens... more The viral envelope glycoproteins are essential for entry into their host cells and studied extensively for designing vaccines. We hypothesize that the glycosylation on the HIV-1 viral envelope glycoprotein 41(gp41) at critical residues offers viral escape from the specific immune surveillant neutralizing antibodies Z13, 4E10 and 10E8 targeted to their linear epitopes in the Membrane Proximal External Region (MPER). The glycosylation occurring on the 50th residue (Asparagine) contained in the target (NWFNIT) can mask itself to be inaccessible for these neutralizing antibodies. The glycosylation rate of the epitopes which are shared by the Z13, 4E10 and 10E8 neutralizing antibodies of HIV-1 were predicited in silico. We analyzed the reliable frequency of glycosylation on the HIV-1 envelope gp41 using prediction tools to unravel the plausibility of the glycosylation by a mannose at 50th residue in the 59 amino acid long HIV-gp41 trimer (PDBID: 2M7W and 2LP7). It is evident that the glycosylation by a mannose that masks these targets is possible only when the 50th amino-acid is N (Asparagine, Asn) which is not possible when N is mutated to D (Aspartatic acid, Asp). The additive advantage for the retrovirus is its error-prone reverse transcriptase which can choose to copy these survivable mutants with Asn N-50 that can be glycosylated as explained by the Copy-choice model. So the glycan shields varying in their intensity and patterns have to be essentially studied to understand the viral escape strategies that will give a way forward towards a successful vaccine that can elicit a neutralizing antibody response to confer protection.
Journal of Molecular Modeling, 2010
Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-ba... more Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. It also acts as a drug target for Leishmaniasis. Inhibition of DHFR leads to cell death through lack of thymine (nucleotide metabolism). Although the crystal structures of Leishmania major and Trypanosoma cruzi DHFR-thymidylate synthase (TS) have been resolved, to date there is no three-dimensional (3D)structural information on DHFR-TS of Leishmania donovani chagasi, which causes visceral leishmaniasis. Our aim in this study was to model the 3D structure of L. donovani chagasi DHFR-TS, and to investigate the structural requirements for its inhibition. In this paper we describe a highly refined homology model of L. donovani chagasi DHFR-TS based on available crystallographic structures by using the Homology module of Insight II. Structural refinement and minimization of the generated L. donovani chagasi DHFR-TS model employed the Discover 3 module of Insight II and molecular dynamic simulations. The model was further validated through use of the PROCHECK, Verify_3D, PROSA, PSQS and ERRAT programs, which confirm that the model is reliable. Superimposition of the model structure with the templates L. major A chain, L. major B chain And T. cruzi A chain showed root mean square deviations of 0.69 Å, 0.71 Å and 1.11 Å, respectively. Docking analysis of the L. donovani chagasi DHFR-TS model with methotrexate enabled us to identify specific residues, viz. Val156, Val30, Lys95, Lys75 and Arg97, within the L. donovani chagasi DHFR-TS binding pocket, that play an important role in ligand or substrate binding. Docking studies clearly indicated that these five residues are important determinants for binding as they have strong hydrogen bonding interactions with the ligand.
Journal of Materials Engineering and Performance, 2006
The dry sliding wear behavior of Al 2219 alloy and Al 2219/SiCp/Gr hybrid composites are investig... more The dry sliding wear behavior of Al 2219 alloy and Al 2219/SiCp/Gr hybrid composites are investigated under similar conditions. The composites are fabricated using the liquid metallurgy technique. The dry sliding wear test is carried out for sliding speeds up to 6 m/s and for ...
Journal of Computer-Aided Molecular Design, 2010
The ability to identify fragments that interact with a biological target is a key step in FBDD. T... more The ability to identify fragments that interact with a biological target is a key step in FBDD. To date, the concept of fragment based drug design (FBDD) is increasingly driven by bio-physical methods. To expand the boundaries of QSAR paradigm, and to rationalize FBDD using In silico approach, we propose a fragment based QSAR methodology referred here in as FB-QSAR. The FB-QSAR methodology was validated on a dataset consisting of 52 Hydroxy ethylamine (HEA) inhibitors, disclosed by GlaxoSmithKline Pharmaceuticals as potential anti-Alzheimer agents. To address the issue of target selectivity, a major confounding factor in the development of selective BACE1 inhibitors, FB-QSSR models were developed using the reported off target activity values. A heat map constructed, based on the activity and selectivity profile of the individual R-group fragments, and was in turn used to identify superior R-group fragments. Further, simultaneous optimization of multiple properties, an issue encountered in real-world drug discovery scenario, and often overlooked in QSAR approaches, was addressed using a Multi Objective (MO-QSPR) method that balances properties, based on the defined objectives. MO-QSPR was implemented using Derringer and Suich desirability algorithm to identify the optimal level of independent variables (X) that could confer a trade-off between selectivity and activity. The results obtained from FB-QSAR were further substantiated using MIF (Molecular Interaction Fields) studies. To exemplify the potentials of FB-QSAR and MO-QSPR in a pragmatic fashion, the insights gleaned from the MO-QSPR study was reverse engineered using Inverse-QSAR in a combinatorial fashion to enumerate some prospective novel, potent and selective BACE1 inhibitors.
Journal of Chemical Information and Modeling, 2009
BACE1, also called-secretase or memapsin 2, is an extensively studied aspartic protease, involved... more BACE1, also called-secretase or memapsin 2, is an extensively studied aspartic protease, involved in etiopathogenesis and progression of Alzheimer's disease (AD). We report herein a modified structure-based virtual screening protocol that augments the lead identification process against BACE1 during virtual screening endeavors. A hybrid structure-based virtual screening protocol that incorporates elements from both ligandbased and structure-based techniques was used for the identification of prospective small molecule inhibitors. Virtual screening, using an active-site-derived pharmacophore, followed by ROCS (rapid overlay of chemical structures)-based GOLD (genetic optimization in ligand docking) docking was used to identify a library of focused candidates. The efficacy of the ROCS-based GOLD docking method together with our customized weighted consensus scoring function was evaluated against conventional docking methods for its ability to discern true positives from a screening library. An in-depth structural analysis of the binding mode of the top-ranking molecules reveals that emulation of the curial interaction patterns deemed necessary for BACE1 inhibition. The results obtained from our validation study ensure the superiority of our docking methodology over conventional docking methods in yielding higher enrichment rates.
Journal of Chemical Information and Modeling, 2009
Journal of Chemical Information and Modeling, 2012
International Journal of Machining and Machinability of Materials, 2006
500 Int. J. Machining and Machinability of Materials, Vol. 1, No. 4, 2006 ... Analysis of burr fo... more 500 Int. J. Machining and Machinability of Materials, Vol. 1, No. 4, 2006 ... Analysis of burr formation during drilling of hybrid metal matrix composites using design of experiments ... Department of Mechanical Engineering, PSG College of Technology, Coimbatore 641 004, India Fax: ...
International Journal of Machine Tools and Manufacture, 2007
The main concern in the present study is the surface roughness variations on the drilled surface ... more The main concern in the present study is the surface roughness variations on the drilled surface and extension of surface and subsurface deformation due to drilling. The influence of different tools and cutting conditions on Al2219/15%SiCp and Al2219/15%SiCp-3%Graphite (hybrid) composites is investigated experimentally. The composites are fabricated by liquid metallurgy method. The drilling tests are conducted with carbide and coated carbide tools. The surface roughness decreases with the increase in cutting speed and increases with the increase in feed rate. The surface is analyzed using scanning electron microscope (SEM). Microhardness profiles indicate that the subsurface deformation extends up to a maximum of 120 mm below the machined surface for Al2219/15SiCp-3Gr composite when compared to 150 mm in Al2219/15SiCp composite.
The International Journal of Advanced Manufacturing Technology, 2006
Abstract This paper presents the influence of cutting parameters on thrust force, surface finish,... more Abstract This paper presents the influence of cutting parameters on thrust force, surface finish, and burr forma-tion in drilling Al2219/15SiCp and Al2219/15SiCp-3Gr composites. The composites were fabricated using the liquid metallurgy method. The tools used were ...
Antimicrobial Agents and Chemotherapy, 2011
ABSTRACTNovel antileishmanials are urgently required to overcome emergence of drug resistance, cy... more ABSTRACTNovel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects onL. donovanipromastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effectivein vitroand demonstrated strong efficaciesin vivothrough the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistantLeishmania donovanistrains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxyge...
Journal of Molecular Graphics and Modelling, 2018
The organophosphorus hydrolase enzyme is involved in the catalyzing reaction that involve hydroly... more The organophosphorus hydrolase enzyme is involved in the catalyzing reaction that involve hydrolysis of organophosphate toxic compounds. An enzyme from Deinococcus radiodurans reported as homologous to phosphotriesterase and show activity against organophosphate. In the past activity of this enzyme is low and efforts made to improve the activity by experimental mutation study. However only very few organophosphates tested against very few catalytic site mutations. In order to improve the catalytic power of the organophosphorus hydrolase enzyme, we carried out systematic functional hotspot based protein engineering strategy. The mutants tested against 46 know organophosphate compounds using molecular docking study. Finally, we carried out an extensive molecular docking study to predict the binding of 46 organophosphate compounds to wild-type protein and mutant organophosphorus hydrolase enzyme. At the end we are able to improve the degrading potential of organophosphorus hydrolase enzyme against organophosphate toxic compounds. This preliminary study and the outcome would be useful guide for the experimental scientist involved in the bioremediation of toxic organophosphate compounds.
Bioinformation, 2018
Geminiviridae is a large family of circular, single stranded DNA viruses, which infects and cause... more Geminiviridae is a large family of circular, single stranded DNA viruses, which infects and causes devastating diseases on economically important crops. They are subdivided into nine genera. Members of the genus begomovirus encode a pathogenic protein called AC2/C2whichinteracts that inactivates many plant proteins and trans-activates a number of host genes via the C-terminal transactivation domain. Hence, a sequence analysis on C-terminal region of AC2/C2 was completed. Analysis of 124 bipartite and 463 mono partite begomo viral AC2/C2 proteins revealed major differences in protein length, composition and position of acidic, aromatic and hydrophobic residues. Secondary structure analysis of AC2/C2 revealed the possible formation of C-terminal α-helix, which is similar to the acidic activation domain of many transcriptional activator proteins. Previous studies demonstrated that AC2 utilizes conserved late element (CLE) for the transactivation of viral genes and genome-wide mapping of same consensus in A. thaliana yielded 122 promoters with exact CLE consensus sequence. Analysis of protein interaction network for 106 CLE containing genes, 87 AC2 trans activated genes and 10 AC2 interacting proteins revealed a possible regulation of hundreds of host proteins which helps begomoviruses to produce a successful viral infection.
The divergence in catalytic actions of N-acetyl neuraminic lyase (NAL) superfamily proteins, all ... more The divergence in catalytic actions of N-acetyl neuraminic lyase (NAL) superfamily proteins, all of which have pyruvate as a substrate, suggests common ancestry. Lack of catalytic triad residues essential for binding pyruvate in annotated DHDPS proteins from Gram+ve B.clausii (PDBid-3E96) and O.hiyensis (PDBid-3D0C) indicated that these proteins are inactive and therefore could be possible early ancestors. Analysis revealed that the most appropriate cavity of these proteins is voluminous and has an elongated topography compared to the trimmed side-wise tilted cavity topography in all other NAL superfamily proteins. Strength and the morphology of the interface regions contouring the cavity are the significant determinants of the topography. It is possible that evolutionary forces led to modulation of the structural segments following the beta strand 5 and alpha helix 10, which are significant participants of interfacial regions. Major structural motions captured by molecular dynamics...
Bioorganic & Medicinal Chemistry Letters, 2017
Hitherto this is the first report pertaining to production of biofilm inhibitory compound(s) (BIC... more Hitherto this is the first report pertaining to production of biofilm inhibitory compound(s) (BIC) from Bacillus subtilis BR4 against Pseudomonas aeruginosa (ATCC 27853) coupled with production optimization. In order to achieve this, combinations of media components were formulated by employing statistical tools such as Plackett-Burman analysis and central composite rotatable design. It was evident that at 35 ml L-1 glycerol and 3.8 g L-1 casamino acid, anti-biofilm activity and production of extracellular protein significantly increased by 1.5-fold and 1.2-fold, respectively. These results corroborate that the combination of glycerol and casamino acid plays a key role in the production of BIC. Further, metabolic profiling of BIC was carried out using liquid chromatography/tandem mass spectrometry (LC-MS/MS) based on m/z value. The presence of Stigmatellin Y was predicted with monoisotopic neutral mass of 484.2825 Da. In support of optimization study, higher production of BIC was confirmed in the optimized-media-grown BR4 (OPT-BR4) than in the ideal-media-grown BR4 (ID-BR4) by LC-MS/MS analysis. PqsR in P. aeruginosa is a potential target for anti-virulent therapy. Molecular docking study has revealed that Stigmatellin Y interacts with PqsR in the similar orientation like a cognate signal (PQS) and synthetic inhibitor. In addition, Stigmatellin Y was found to exhibit interaction with four more amino acid residues of PqsR to establish strong affinity. Stigmatellin Y thus might play a role of competitor for PQS to distract PQS-PqsR mediated communication in P. aeruginosa. The present investigation thus paves new avenues to develop anti-Pseudomonas virulent therapy.
Journal of biomolecular structure & dynamics, Jan 12, 2017
More than 100 years of research on Alzheimer's disease didn't yield a potential cure for ... more More than 100 years of research on Alzheimer's disease didn't yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P-glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable. Identification and understanding of protein-ligand interactions are essential for ligand optimization process. Structure-based drug design (SBDD) efforts led to a steady accumulation of BACE1-ligand crystal complexes in the PDB. This study focuses on analyses of 153 BACE1-ligand complexes for the direct contacts (hydrogen bonds and weak interactions) observed between protein and ligand and indirect contacts (water-mediated hydrogen bonds), observed in BACE1-ligand complex crystal structures. Intraligand hydrogen bonds were analyzed, with focus...
Journal of Biomolecular Structure and Dynamics, 2016
The β-strand forming outer membrane proteins (OMPs) are found in the outer membrane of the Gram n... more The β-strand forming outer membrane proteins (OMPs) are found in the outer membrane of the Gram negative bacteria, eukaryotic organelles of prokaryotic origin, mitochondria, and chloroplasts. The OMPs present in the outer membrane plays a vital role in the maintenance of cell homeostasis. Two classes of OMPs were recognized within the outer membrane, one is peripheral and another is integral membrane proteins with unique β-barrel fold architecture. In Gram negative bacteria, OMPs are classified into six families based on the function (Koebnik, Locher, & Van Gelder, 2000). There are general porins (OMPC, OMPF, and PhoE), passive transporters (LamB, ScrY, FadL, and TodX), active transporters (siderophores transporters FepA, FecA, Fhu A, and vitamin B12 transporters BtuB), enzymes (phospholipase OmpLA or protease OmpT), defensive proteins (OmpX), and structural proteins (OmpA). Understanding the structure and function of OMPs is of critical importance, in the antibiotic design and development. In an antibacterial therapy, one of the main steps for the antibiotic is to cross the outer membrane through OMPs like OMPF present in S. typhi (Balasubramaniam, Arockiasamy, Kumar, Sharma, & Krishnaswamy, 2012). Most of the antibiotic targets are present within the bacterial cell; the antibiotics are known to take two routes to reach the targets. The hydrophobic antibiotics pass through the lipid and the hydrophilic molecules translocate through water-filled porins. The lipid and protein compositions of the outer membrane have a strong impact on the permeability of antibiotics and drug resistance. So, studies conducted on physico-chemical properties of amino acid residues along the pores and by considering the lipid–OMP interactions may provide valuable insights into the antibiotic resistance. Liposomeswelling assay is used to qualitatively characterize antibiotic translocation through porin. Later quantitative electrophysiology measurements were used. The OMPmediated antibiotic permeability is still not clearly understood. The availability of high resolution porin structure and further investigation on this reveals that antibiotic translocates by interacting with the surface of the channel. Ampicillin-binding site in the channel of OMPF is identified. Facilitated diffusion through a binding site was observed in maltoporin (Danelon, Brando, & Winterhalter, 2003). Computational molecular dynamics (MD) studies in the past have shed light on the antibiotic translocation process (Kumar et al., 2010). Moreover, the alteration or modification of porin expression is associated with antimicrobial resistance. The emergence of porin-related antibiotic resistance is a challenge for designing better antibiotics (Beceiro, Tomas, & Bou, 2013; Nikaido, 2003). There are limited studies on relating computational modeling/dynamics with experiments. A search on pubmed results in only 150 hits in which very few are interesting. An interesting work by Kumar et al., demonstrates the structural and dynamical properties of the two major porins (OmpF and OmpC) in Escherichia coli, using MD simulations and showed the relationship between pore amino acid properties and antibiotic transport (Kumar, Hajjar, Ruggerone, & Ceccarelli, 2010). They presented the results of transport properties using accelerated MD simulations to probe the diffusion of norfloxacin (a fluoroquinolone antibiotic) through the two porins OmpF/OmpC. Porins perform various functions by depending upon channels, regulation of porin expression and its structure. Although OMPs are commonly made of β-strands, it is interesting to observe the variety of completely different functions, that is been performed such as diffusion pores, substrate-specific transporters, signal transduction, and enzymatic activity. The transport of various substances
Molecular diversity, 2012
γ-Secretase (Gamma Secretase) is a potential drug target in Alzheimer's disease therapeutics.... more γ-Secretase (Gamma Secretase) is a potential drug target in Alzheimer's disease therapeutics. A sequel lead design study was undertaken on a series of bicyclononanes with an aim of identifying potent isofunctional chemotypes. Fragment-based bioisosteric replacement, which considers shape, chemistry, and electrostatics was carried out to mine over four million medicinally relevant fragments of Brood database. The resulting subset, thus, obtained was further mined using consensus QSAR developed from 2D and CoMFA, CoMSIA, GRIND (3D) QSAR predicted endpoints with superior statistical results. The employed consensus prediction and the predicted endpoint values were found to be in good agreement with the experimental values. The predictive ability of the generated model was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. Few analogs designed, using the concept of bioisosterism, were found to be...
Bioinformation, 2015
The viral envelope glycoproteins are essential for entry into their host cells and studied extens... more The viral envelope glycoproteins are essential for entry into their host cells and studied extensively for designing vaccines. We hypothesize that the glycosylation on the HIV-1 viral envelope glycoprotein 41(gp41) at critical residues offers viral escape from the specific immune surveillant neutralizing antibodies Z13, 4E10 and 10E8 targeted to their linear epitopes in the Membrane Proximal External Region (MPER). The glycosylation occurring on the 50th residue (Asparagine) contained in the target (NWFNIT) can mask itself to be inaccessible for these neutralizing antibodies. The glycosylation rate of the epitopes which are shared by the Z13, 4E10 and 10E8 neutralizing antibodies of HIV-1 were predicited in silico. We analyzed the reliable frequency of glycosylation on the HIV-1 envelope gp41 using prediction tools to unravel the plausibility of the glycosylation by a mannose at 50th residue in the 59 amino acid long HIV-gp41 trimer (PDBID: 2M7W and 2LP7). It is evident that the glycosylation by a mannose that masks these targets is possible only when the 50th amino-acid is N (Asparagine, Asn) which is not possible when N is mutated to D (Aspartatic acid, Asp). The additive advantage for the retrovirus is its error-prone reverse transcriptase which can choose to copy these survivable mutants with Asn N-50 that can be glycosylated as explained by the Copy-choice model. So the glycan shields varying in their intensity and patterns have to be essentially studied to understand the viral escape strategies that will give a way forward towards a successful vaccine that can elicit a neutralizing antibody response to confer protection.
Journal of Molecular Modeling, 2010
Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-ba... more Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. It also acts as a drug target for Leishmaniasis. Inhibition of DHFR leads to cell death through lack of thymine (nucleotide metabolism). Although the crystal structures of Leishmania major and Trypanosoma cruzi DHFR-thymidylate synthase (TS) have been resolved, to date there is no three-dimensional (3D)structural information on DHFR-TS of Leishmania donovani chagasi, which causes visceral leishmaniasis. Our aim in this study was to model the 3D structure of L. donovani chagasi DHFR-TS, and to investigate the structural requirements for its inhibition. In this paper we describe a highly refined homology model of L. donovani chagasi DHFR-TS based on available crystallographic structures by using the Homology module of Insight II. Structural refinement and minimization of the generated L. donovani chagasi DHFR-TS model employed the Discover 3 module of Insight II and molecular dynamic simulations. The model was further validated through use of the PROCHECK, Verify_3D, PROSA, PSQS and ERRAT programs, which confirm that the model is reliable. Superimposition of the model structure with the templates L. major A chain, L. major B chain And T. cruzi A chain showed root mean square deviations of 0.69 Å, 0.71 Å and 1.11 Å, respectively. Docking analysis of the L. donovani chagasi DHFR-TS model with methotrexate enabled us to identify specific residues, viz. Val156, Val30, Lys95, Lys75 and Arg97, within the L. donovani chagasi DHFR-TS binding pocket, that play an important role in ligand or substrate binding. Docking studies clearly indicated that these five residues are important determinants for binding as they have strong hydrogen bonding interactions with the ligand.
Journal of Materials Engineering and Performance, 2006
The dry sliding wear behavior of Al 2219 alloy and Al 2219/SiCp/Gr hybrid composites are investig... more The dry sliding wear behavior of Al 2219 alloy and Al 2219/SiCp/Gr hybrid composites are investigated under similar conditions. The composites are fabricated using the liquid metallurgy technique. The dry sliding wear test is carried out for sliding speeds up to 6 m/s and for ...
Journal of Computer-Aided Molecular Design, 2010
The ability to identify fragments that interact with a biological target is a key step in FBDD. T... more The ability to identify fragments that interact with a biological target is a key step in FBDD. To date, the concept of fragment based drug design (FBDD) is increasingly driven by bio-physical methods. To expand the boundaries of QSAR paradigm, and to rationalize FBDD using In silico approach, we propose a fragment based QSAR methodology referred here in as FB-QSAR. The FB-QSAR methodology was validated on a dataset consisting of 52 Hydroxy ethylamine (HEA) inhibitors, disclosed by GlaxoSmithKline Pharmaceuticals as potential anti-Alzheimer agents. To address the issue of target selectivity, a major confounding factor in the development of selective BACE1 inhibitors, FB-QSSR models were developed using the reported off target activity values. A heat map constructed, based on the activity and selectivity profile of the individual R-group fragments, and was in turn used to identify superior R-group fragments. Further, simultaneous optimization of multiple properties, an issue encountered in real-world drug discovery scenario, and often overlooked in QSAR approaches, was addressed using a Multi Objective (MO-QSPR) method that balances properties, based on the defined objectives. MO-QSPR was implemented using Derringer and Suich desirability algorithm to identify the optimal level of independent variables (X) that could confer a trade-off between selectivity and activity. The results obtained from FB-QSAR were further substantiated using MIF (Molecular Interaction Fields) studies. To exemplify the potentials of FB-QSAR and MO-QSPR in a pragmatic fashion, the insights gleaned from the MO-QSPR study was reverse engineered using Inverse-QSAR in a combinatorial fashion to enumerate some prospective novel, potent and selective BACE1 inhibitors.
Journal of Chemical Information and Modeling, 2009
BACE1, also called-secretase or memapsin 2, is an extensively studied aspartic protease, involved... more BACE1, also called-secretase or memapsin 2, is an extensively studied aspartic protease, involved in etiopathogenesis and progression of Alzheimer's disease (AD). We report herein a modified structure-based virtual screening protocol that augments the lead identification process against BACE1 during virtual screening endeavors. A hybrid structure-based virtual screening protocol that incorporates elements from both ligandbased and structure-based techniques was used for the identification of prospective small molecule inhibitors. Virtual screening, using an active-site-derived pharmacophore, followed by ROCS (rapid overlay of chemical structures)-based GOLD (genetic optimization in ligand docking) docking was used to identify a library of focused candidates. The efficacy of the ROCS-based GOLD docking method together with our customized weighted consensus scoring function was evaluated against conventional docking methods for its ability to discern true positives from a screening library. An in-depth structural analysis of the binding mode of the top-ranking molecules reveals that emulation of the curial interaction patterns deemed necessary for BACE1 inhibition. The results obtained from our validation study ensure the superiority of our docking methodology over conventional docking methods in yielding higher enrichment rates.
Journal of Chemical Information and Modeling, 2009
Journal of Chemical Information and Modeling, 2012
International Journal of Machining and Machinability of Materials, 2006
500 Int. J. Machining and Machinability of Materials, Vol. 1, No. 4, 2006 ... Analysis of burr fo... more 500 Int. J. Machining and Machinability of Materials, Vol. 1, No. 4, 2006 ... Analysis of burr formation during drilling of hybrid metal matrix composites using design of experiments ... Department of Mechanical Engineering, PSG College of Technology, Coimbatore 641 004, India Fax: ...
International Journal of Machine Tools and Manufacture, 2007
The main concern in the present study is the surface roughness variations on the drilled surface ... more The main concern in the present study is the surface roughness variations on the drilled surface and extension of surface and subsurface deformation due to drilling. The influence of different tools and cutting conditions on Al2219/15%SiCp and Al2219/15%SiCp-3%Graphite (hybrid) composites is investigated experimentally. The composites are fabricated by liquid metallurgy method. The drilling tests are conducted with carbide and coated carbide tools. The surface roughness decreases with the increase in cutting speed and increases with the increase in feed rate. The surface is analyzed using scanning electron microscope (SEM). Microhardness profiles indicate that the subsurface deformation extends up to a maximum of 120 mm below the machined surface for Al2219/15SiCp-3Gr composite when compared to 150 mm in Al2219/15SiCp composite.
The International Journal of Advanced Manufacturing Technology, 2006
Abstract This paper presents the influence of cutting parameters on thrust force, surface finish,... more Abstract This paper presents the influence of cutting parameters on thrust force, surface finish, and burr forma-tion in drilling Al2219/15SiCp and Al2219/15SiCp-3Gr composites. The composites were fabricated using the liquid metallurgy method. The tools used were ...
Antimicrobial Agents and Chemotherapy, 2011
ABSTRACTNovel antileishmanials are urgently required to overcome emergence of drug resistance, cy... more ABSTRACTNovel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects onL. donovanipromastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effectivein vitroand demonstrated strong efficaciesin vivothrough the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistantLeishmania donovanistrains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxyge...