Durg Vijay Singh - Academia.edu (original) (raw)

Papers by Durg Vijay Singh

Pesticide Research Journal, 2018

Protein tyrosine phosphatase 1B (PTP1B) has been identified as a negative regulator of insulin an... more Protein tyrosine phosphatase 1B (PTP1B) has been identified as a negative regulator of insulin and leptin signalling pathway; hence, it can be considered as a new therapeutic target of intervention for the treatment of type 2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e. diabestiy. In order to get more information on identification and optimization of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold. A six-point pharmacophore model consisting of three hydrogen bond acceptor (A), one negative ionic (N) and two aromatic rings (R) with discrete geometries as pharmacophoric features were developed for a predictive 3D QSAR model. The probable binding conformation of the ligands within the active site was studied through molecular docking. The molecular interactions and the structural features responsible for PTP1B inhibition and sele...

P. minor is a major weed of wheat crop which has evolved resistance against herbicides. Isoprotur... more P. minor is a major weed of wheat crop which has evolved resistance against herbicides. Isoproturon is the most accepted herbicide developed in 1992. Later, introduced herbicides also developed resistance and cross-resistance to their respective binding sites. Isoproturon binds at the QB binding site of the D1 protein of photosystem-II (PS-II) which blocks the electron transfer in photosynthesis. In this work, a series of computational studies have been implemented to discover herbicides against the D1 protein of P. minor. Through computational study, twenty-four lead molecules are reported which have shown a higher binding affinity and inhibition constant compared to the reference ligand. The conformational stability of docked complexes was evaluated by molecular dynamics simulation and MM/PBSA method. Ala225, Ser226, Phe227, and Asn229 present in the binding site of protein play an important role in the stability of the protein-lead complex via hydrogen bond interaction and pi-pi ...

Mini-Reviews in Medicinal Chemistry, 2020

: Parasite Plasmodium falciparum is continuously giving a challenge to human beings by changing i... more : Parasite Plasmodium falciparum is continuously giving a challenge to human beings by changing itself against most of the antimalarial drugs and its consequences can be seen in the form of a huge number of deaths each year especially in the poor and developing country. Due to its drug resistance ability, new drugs are regularly needed to kill the organism. Many new drugs have been developed based on different mechanisms. One of the potential mechanisms is to hamper protein synthesis by blocking the gene expression. : S-Adenosyl-L-homocysteine (SAH) hydrolase is a NAD+ dependent tetrameric enzyme, which is responsible for the reversible hydrolysis of AdoHcy to adenosine and L-homocysteine, has been recognized as a new target for antimalarial agents since the parasite has a specific SAH hydrolase. The inhibition of SAH hydrolase causes the intracellular accumulation of S-Adenosyl-L-homocysteine, elevating the ratio of SAH to S-adenosylmethionine (SAM) and inhibiting SAM-dependent methyltransferase that catalyzes methylation of the capped structure at the 5′-terminus of mRNA, and other methylation reaction which is essential for parasite proliferation. In other words, S-Adenosyl-Lhomocysteine hydrolase regulates methyltransferase reactions. In this way, SAH hydrolase inhibitors can be used for the treatment of different diseases like malaria, cancer, viral infection, etc. by ultimately stopping the synthesis of protein. Many antiviral drugs have been synthesized and marketed which are based on the inhibition of SAH hydrolase. : This review summarises the development of SAH inhibitors developed over the last 20 years and their potentiality for the treatment of malaria.

Network Modeling Analysis in Health Informatics and Bioinformatics, 2019

Phalaris minor (P. minor) is a major weed of wheat crop. It has developed resistance as well as c... more Phalaris minor (P. minor) is a major weed of wheat crop. It has developed resistance as well as cross-resistance against aryloxyphenoxypropionates (FOP) and cyclohexanediones (DIM) group of herbicides, probably due to mutations in the binding site of acetyl-CoA carboxylase (ACCase) at its carboxyl transferase domain (CT-domain). Binding of FOP and DIM group of herbicides inhibits de novo synthesis of fatty acids, which is essential for survival of P. minor. This work highlights atomistic details of binding mode of diclofop (FOP) and tepraloxydim (DIM) groups of herbicides in the CT-domain of modelled P. minor ACCase protein. Molecules have been extracted from ZINC database based upon their 2D structural similarities with existing FOP and DIM groups of herbicides, which has been further screened at FOP-and DIM-binding sites of the modelled protein. Rigid and flexible docking has been performed to prioritise hits considering the diclofop and tepraloxydim as a reference. Finally, two molecules of the FOP group and three molecules of DIM group have been obtained that have shown better predicted binding affinity, ligand efficiency, and inhibition constant as compared to the reference molecules. Molecular dynamics simulation of about 10 ns was performed for both the reference molecules as well as for all the five prioritised molecules to determine their conformational stability and prominent H-bond network. Amino acid residues A56 and I160 of D1 protein are equivalent to A1705 and I1181 amino acids of black grass, as well as A1627 and I1735 amino acids of yeast (PDB ID: 1UYR) forms invariant hydrogen bond with reference and screened molecules. It was concluded that common binding features of FOP and DIM may be utilised for development of bitopic herbicide.

Network Modeling Analysis in Health Informatics and Bioinformatics, 2018

Curcumin, a golden yellow pigment present in the spice turmeric, has pleiotropic chemopreventive ... more Curcumin, a golden yellow pigment present in the spice turmeric, has pleiotropic chemopreventive and therapeutic active compound against many diseases including cancer. It has been reported that curcumin acts as a topoisomerase II inhibitor and it was found that even concentration of 50 µM of curcumin in vitro is active in a similar fashion as etoposide (antineoplastic agent). Topoisomerases (type I and type II) are enzymes that regulate the overwinding or underwinding of DNA by cutting the phosphate bond of one or two strands of DNA, respectively. Topoisomerase II was selected as target, since it affects both strands of DNA. The present in silico study about designing curcumin analogues as better inhibitors of topoisomerase visà-vis curcumin is based on ADME filtering and docking simulation using Schrödinger suite. The docking simulation result suggested that out of 1000 designed curcumin analogues using ligbuilder tool and curcumin as a lead, 293 screened analogues show good binding affinity at the active site of Human DNA topoisomerase II in comparison to known drug Salvicine. The top five analogues with best binding affinity was shown by ligand1_826, ligand1_758, ligand1_976, ligand1_956 and ligand1_827 with glide scores − 16.70, − 16.03, − 15.45, − 15.43 and − 15.09, respectively. Therefore it is possible that screened curcumin analogues can be used as lead molecules for screening of ligand database and future chemopreventive agents.

Journal of Biomolecular Structure and Dynamics, 2017

ATP-Binding cassette (ABC) transporters play an extensive role in the translocation of diverse se... more ATP-Binding cassette (ABC) transporters play an extensive role in the translocation of diverse sets of biologically important molecules across membrane. EchnocandinB (antifungal) and EcdL protein of Aspergillus rugulosus are encoded by the same cluster of genes. Co-expression of EcdL and echinocandinB reflects tightly linked biological functions. EcdL belongs to Multidrug Resistance associated Protein (MRP) subfamily of ABC transporters with an extra transmembrane domain zero (TMD0). Complete structure of MRP subfamily comprising of TMD0 domain, at atomic resolution is not known. We hypothesized that the transportation of echonocandinB is mediated via EcdL protein. Henceforth, it is pertinent to know the topological arrangement of TMD0, with other domains of protein and its possible role in transportation of echinocandinB. Absence of effective template for TMD0 domain lead us to model by I-TASSER, further structure has been refined by multiple template modelling using homologous templates of remaining domains (TMD1, NBD1, TMD2, NBD2). The modelled structure has been validated for packing, folding and stereochemical properties. MD simulation for 0.1 μs has been carried out in the biphasic environment for refinement of modelled protein. Non-redundant structures have been excavated by clustering of MD trajectory. The structural alignment of modelled structure has shown Z-score -37.9; 31.6, 31.5 with RMSD; 2.4, 4.2, 4.8 with ABC transporters; PDB ID 4F4C, 4M1 M, 4M2T, respectively, reflecting the correctness of structure. EchinocandinB has been docked to the modelled as well as to the clustered structures, which reveals interaction of echinocandinB with TMD0 and other TM helices in the translocation path build of TMDs.

The journal of physical chemistry. B, Jan 23, 2017

A comparative study of binding interaction between Safranin O (SO) and Neutral Red (NR) with lyso... more A comparative study of binding interaction between Safranin O (SO) and Neutral Red (NR) with lysozyme (Lyz) has been reported using several spectroscopic methods along with computational approaches. Steady-state fluorescence measurements revealed static quenching as the major quenching mechanism in Lyz-SO and Lyz-NR interaction, which is further supported by time-resolved fluorescence and UV-vis measurements. Additionally, binding and thermodynamic parameters of these interactions are calculated from temperature dependent fluorescence data. Moreover, conformational changes of protein upon binding with SO and NR are provided by synchronous and circular dichroism (CD) measurements. Molecular docking study provided the exact binding location of SO and NR in lysozyme. Along with this study, molecular dynamics simulation is carried out to measure the stability of Lyz, Lyz-SO, and Lyz-NR complex. The present study revealed the strong binding affinity of dyes with lysozyme, and this study ...

Journal of biomolecular structure & dynamics, Jan 10, 2017

Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and ... more Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signalling pathway, hence it can be considered as a new therapeutic target of intervention for the treatment of type2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e., diabestiy. In order to get more information on identification and optimisation of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold. A six-point pharmacophore model consisting of three hydrogen bond acceptor (A), one negative ionic (N) and two aromatic rings (R) with discrete geometries as pharmacophoric features were developed for a predictive 3D QSAR model. The probable binding conformation of the ligands within the active site was studied through molecular docking. The molecular interactions and the structural features responsible for PTP1B inhibition and selecti...

http://www.indianjournals.com/ijor.aspx?target=ijor:ijws&volume=36&issue=3and4&article=026

Singh DV & Misra K, Comparative study of Binding mode of Curcuminoids at the active site of Thior... more Singh DV & Misra K, Comparative study of Binding mode of Curcuminoids at the active site of Thioredoxine Reductase: Design and synthesis of Anti-cancer drugs. In: Antimicrobial Resistance: from emerging threat to realty. Editors: Rubina et al. Narosa Publishing House, New Delhi. (2009) pp 290-295 ISBN 978-81-8487-060-2

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences, 2014

Permeability or P-glycoprotein (P-gp), present in both prokaryotes and eukaryotes is an essential... more Permeability or P-glycoprotein (P-gp), present in both prokaryotes and eukaryotes is an essential protein belonging to the adenosine triphosphate (ATP) binding cassette transporter family. It functions as a protective barrier by extrusion of wide range of substrates including toxins, xenobiotic compounds and drugs from the cell. These are ubiquitous integral membrane proteins that have ATPase activity for substrate transport across the lipid membrane. The potential role of P-gp in efflux mechanism is to avoid drug accumulation and to provide intrinsic resistance to a broad range of anticancer compounds against sarcoma, breast cancer and certain types of leukemia. This review recapitulates the structural and functional aspects of core domains of P-gp. Furthermore, various proposed mechanisms of translocation of substrates across the membrane which explain the conformational changes in different domains upon ATP binding and hydrolysis. Another critical aspect focuses on different modulators and their mode of binding on P-gp which facilitates the inhibition of efflux mechanism. Ten models of drug efflux mechanism have been illustrated and a comparative account of their applicability and limitations given, paving way for further improvements. In the present study it has been observed that contrary to the earlier reported models where transmembrane domain is the preferred binding site of ligands resulting in their efflux through ATP hydrolysis at nucleotide binding domain (NBD) site. The more hydrophilic NBD appears to be the appropriate binding site for majority of the hydrophobic third and fourth generation modulators thus inhibiting the binding and hydrolysis of ATP resulting in inhibition of efflux.

Bioinformation, 2009

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thi... more Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 Å from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.

Journal of vector borne diseases

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are respons... more Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate...

Organic and medicinal chemistry letters, Jan 4, 2012

The plasma membrane redox system (PMRS) has extensively been studied in erythrocytes. The PMRS pl... more The plasma membrane redox system (PMRS) has extensively been studied in erythrocytes. The PMRS plays an important role in maintaining plasma redox balance and provides a protective mechanism against oxidative stress. Earlier it was proposed that only NADH or NADPH provided reducing equivalents to PMRS; however, now it is acknowledged that some polyphenols also have the ability to donate reducing equivalents to PMRS. Two different docking simulation softwares, Molegro Virtual Docker and Glide were used to study the interaction of certain plant polyphenols viz. quercetin, epigallocatechin gallate, catechin epicatechin and resveratrol with human erythroyte NADH-cytochrome b5 reductase, which is a component of PMRS and together with the identification of minimum pharmacophoric feature using Pharmagist. The derived common minimum pharmacophoric features show the presence of minimum bioactive component in all the selected polyphenols. Our results confirm wet lab findings which show that t...

In order to enhance the bioavailability of curcumin its conjugates with piperic acid and glycine ... more In order to enhance the bioavailability of curcumin its conjugates with piperic acid and glycine were synthesized by esterifying the 4 and 4' phenolic hydroxyls, the sites of metabolic conjugation. Antiproliferative and apoptotic efficacy of synthesized conjugates was investigated in MCF-7 and MDA-MB-231 cell lines. IC 50 values of di-O-glycinoyl (CDG) and di-O-piperoyl (CDP) esters of curcumin were found to be comparable with that of curcumin. Both conjugates induced chromatin condensation fragmentation and apoptotic body formation. CDP exposure to MCF-7 cells induced apoptosis initiating loss of mitochondrial membrane potential (∆ψm) followed by inhibition of translocation of transcription factor NF-kB and release of Cytochrome-C. Reactive oxygen species (ROS) production was evaluated by fluorescent activated cell sorter. Change in ratio of Bcl2/ Bclxl was observed, suggesting permeablization of mitochondrial membrane leading to the release of AIF, Smac and other apoptogenic molecules. DNA fragmentation as a hallmark for apoptosis was monitored by TUNEL as well as agrose gel electrophoresis. Thus, it was proven that conjugation does not affect the therapeutic potential of parent molecule in vitro, while these could work in vivo as prodrugs with enhanced pharmacokinetic profile. Pharmacokinetics of these molecules under in vivo conditions is a further scope of this study.

Journal of Molecular Modeling, 2014

Curcumin has been reported to be therapeutically active but has poor bioavailability, half life, ... more Curcumin has been reported to be therapeutically active but has poor bioavailability, half life, and high rate of metabolic detoxifcation. Most of the hydrophobic and acidic drugs get transported through human serum albumin (HSA). Binding of drugs to serum protein increases their half-life. The present study is focused to analyze interaction of curcumin with HSA by NMR and docking studies. In order to investigate the binding affinity of curcumin with HSA, NMR based diffusion techniques and docking study have been carried out. We report that curcumin has shown comparable binding affinity value visa -vis standard, the accessible surface area (ASA) of human serum albumin (uncomplexed) and its docked complex with curcumin at both binding sites was calculated and found to be close to that of warfarin and diazepam respectively. Conclusion drawn from our study demonstrates that curcumin interacts with HSA strongly thereby its poor half life is due to high rate of its metabolic detoxification as reported in literature.

Interdisciplinary Sciences: Computational Life Sciences, 2013

The Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (pfSAHH) enzyme has been considered... more The Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (pfSAHH) enzyme has been considered as a potential chemotherapeutic target against malaria due to the amino acid differences found on binding sites of pfSAHH related to human SAHH. It has been reported that noraristeromycin and some curcumin derivatives have potential binding with the largest cavity of pfSAHH, which is also related to the binding with Nicotinamide-Adenine-Dinucleotide (NAD) and Adenosine (ADN). Our present work focuses on docking and ADMET studies to select potential inhibitors of pfSAHH. The binding of the selected inhibitor of the PfSAHH active site was analyzed using Molegro Virtual Docker. In this study, curcumin and its derivatives have been found to have higher binding affinity with pfSAHH than noraristeromycin. Seven amino acid residues Leu53, His54, Thr56, Lys230, Gly397, His398 and Phe407 of pfSAHH involved in binding with curcumin, are the same as those for noraristeromycin, which reveals that curcumin and noraristeromycin bind in the same region of pfSAHH. Curcumin has shown a strong interaction with hydrophobic amino acid residues of pfSAHH. Molecular Docking and ADMET predictions suggest that curcumin can be a potent inhibitor of pfSAHH with ability to modulate the target in comparatively smaller dose. Therefore, curcumin is likely to become a good lead molecule for the development of effective drug against malaria.