Reaz Uddin - Academia.edu (original) (raw)

Papers by Reaz Uddin

Antibiotics

Campylobacter ureolyticus is a Gram-negative, anaerobic, non-spore-forming bacteria that causes g... more Campylobacter ureolyticus is a Gram-negative, anaerobic, non-spore-forming bacteria that causes gastrointestinal infections. Being the most prevalent cause of bacterial enteritis globally, infection by this bacterium is linked with significant morbidity and mortality in children and immunocompromised patients. No information on pan-therapeutic drug targets for this species is available yet. In the current study, a pan-genome analysis was performed on 13 strains of C. ureolyticus to prioritize potent drug targets from the identified core genome. In total, 26 druggable proteins were identified using subtractive genomics. To the best of the authors’ knowledge, this is the first report on the mining of drug targets in C. ureolyticus. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) was selected as a promiscuous pharmacological target for virtual screening of two bacterial-derived natural product libraries, i.e., postbiotics (n = 78) and streptomycin (n = 737) compounds. LpxC inhibito...

Environmental Science and Pollution Research

The ongoing COVID-19 outbreak, initially identified in Wuhan, China, has impacted people all over... more The ongoing COVID-19 outbreak, initially identified in Wuhan, China, has impacted people all over the globe and new variants of concern continue to threaten hundreds of thousands of people. The delta variant (first reported in India) is currently classified as one of the most contagious variants of SARS-CoV-2. It is estimated that the transmission rate of delta variant is 225% times faster than the alpha variant, and it is causing havoc worldwide (especially in the USA, UK, and South Asia). The mutations found in the spike protein of delta variant make it more infective than other variants in addition to ruining the global efficacy of available vaccines. In the current study, an in silico reverse vaccinology approach was applied for multi-epitope vaccine construction against the spike protein of delta variant, which could induce an immune response against COVID-19 infection. Non-toxic, highly conserved, non-allergenic and highly antigenic B-cell, HTL, and CTL epitopes were identified to minimize adverse effects and maximize the efficacy of chimeric vaccines that could be developed from these epitopes. Finally, V1 vaccine construct model was shortlisted and 3D modeling was performed by refinement, docking against HLAs and TLR4 protein, simulation and in silico expression. In silico evaluation showed that the designed chimeric vaccine could elicit an immune response (i.e., cell-mediated and humoral) identified through immune simulation. This study could add to the efforts of overcoming global burden of COVID-19 particularly the variants of concern.

Microorganisms, 2021

Typhoid fever is caused by a pathogenic, rod-shaped, flagellated, and Gram-negative bacterium kno... more Typhoid fever is caused by a pathogenic, rod-shaped, flagellated, and Gram-negative bacterium known as Salmonella Typhi. It features a polysaccharide capsule that acts as a virulence factor and deceives the host immune system by protecting phagocytosis. Typhoid fever remains a major health concern in low and middle-income countries, with an estimated death rate of ~200,000 per annum. However, the situation is exacerbated by the emergence of the extensively drug-resistant (XDR) strain designated as H58 of S. Typhi. The emergence of the XDR strain is alarming, and it poses serious threats to public health due to the failure of the current therapeutic regimen. A relatively newer computational method called subtractive genomics analyses has been widely applied to discover novel and new drug targets against pathogens, particularly drug-resistant ones. The method involves the gradual reduction of the complete proteome of the pathogen, leading to few potential and novel drug targets. Thus,...

Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disorder of the elderly. It is... more Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disorder of the elderly. It is characterized by widespread loss of central cholinergic neuronal function (Butters et al., 1995). The only symptomatic treatment proven to be effective to date is the use of cholinesterase inhibitors (ChEI) to augment surviving cholinergic activity (Giacobini, 2003, Terry & Buccafusco, 2003). Two types of ChE enzyme are found in the Central Nervous System (CNS), acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8). AChE and BuChE share 65% amino acid sequence homology despite being encoded by different genes on human chromosomes 7(7q22) and 3(3q26), respectively (Soreq & Zaku, 1993). Acetylcholinesterase is responsible for the hydrolysis of acetylcholine at the synaptic cleft and the neuromuscular junction in response to nerve action potential (Massoulie et al., 1993) while the BuChE preferentially acts on butyrylcholine, but also hydrolyzes acetylcholin...

Journal of Biomolecular Structure and Dynamics, 2020

Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which i... more Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CL pro) in viral replication and maturation turns it into an attractive target for the development of effective antiviral drugs against SARS and other coronaviruses. At present, there is no standard drug regime nor any vaccine available against the infection. The rapid development and identification of efficient interventions against SARS-CoV-2 remains a major challenge. Based on the available knowledge of closely related coronavirus and their safety profiles, repurposing of existing antiviral drugs and screening of available databases is considered a near term strategic and economic way to contain the SARS-CoV-2 pandemic. Herein, we applied computational drug design methods to identify Chymotrypsin-like protease inhibitors from FDA approved antiviral drugs and our in-house database of natural and drug-like compounds of synthetic origin. As a result three FDA approved drugs (Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CL pro) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.

Pathogens, 2020

Mycobacterium avium complex (MAC) is a major cause of non-tuberculous pulmonary and disseminated ... more Mycobacterium avium complex (MAC) is a major cause of non-tuberculous pulmonary and disseminated diseases worldwide, inducing bronchiectasis, and affects HIV and immunocompromised patients. In MAC, Mycobacterium avium subsp. hominissuis is a pathogen that infects humans and mammals, and that is why it is a focus of this study. It is crucial to find essential drug targets to eradicate the infections caused by these virulent microorganisms. The application of bioinformatics and proteomics has made a significant impact on discovering unique drug targets against the deadly pathogens. One successful bioinformatics methodology is the use of in silico subtractive genomics. In this study, the aim was to identify the unique, non-host and essential protein-based drug targets of Mycobacterium avium subsp. hominissuis via in silico a subtractive genomics approach. Therefore, an in silico subtractive genomics approach was applied in which complete proteome is subtracted systematically to shortli...

Frontiers in Cellular and Infection Microbiology, 2020

Pathogenic microorganisms exploit host metabolism for sustained survival by rewiring its metaboli... more Pathogenic microorganisms exploit host metabolism for sustained survival by rewiring its metabolic interactions. Therefore, several metabolic changes are induced in both pathogen and host cells in the course of infection. A systems-based approach to elucidate those changes includes the integrative use of genome-scale metabolic networks and molecular omics data, with the overall goal of better characterizing infection mechanisms for novel treatment strategies. This review focuses on novel aspects of metabolism-oriented systems-based investigation of pathogen-human interactions. The reviewed approaches are the generation of dual-omics data for the characterization of metabolic signatures of pathogen-host interactions, the reconstruction of pathogen-host integrated genome-scale metabolic networks, which has a high potential to be applied to pathogen-gut microbiota interactions, and the structure-based analysis of enzymes playing role in those interactions. The integrative use of those approaches will pave the way for the identification of novel biomarkers and drug targets for the prediction and prevention of infectious diseases.

International journal of biological macromolecules, Jan 2, 2018

In the recent decades, the interest on glycosidases has dramatically increased, mainly because th... more In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a vital role in many biological processes. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, monocyclic iminosugars, bicyclic iminosugars, thiosugars and carbasugars will be discussed and special attention will be given to the ones that are currently used clinically. This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the patents, relevant research and patent applications filed in the past years in the field. Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research towards developing new generation...

Frontiers in Pharmacology, 2015

Considering the indigenous utilization of Quercus incana Roxb., the present study deals with the ... more Considering the indigenous utilization of Quercus incana Roxb., the present study deals with the investigation of antioxidant, free radical scavenging activity, total phenolic content, and antimicrobial activity of Q. incana Roxb. In vitro antioxidant activity of the plant fractions were determined by 1,1-diphenyl-2-picrylhydrazyl and nitric oxide scavenging method. Total phenolic contents were determined by gallic acid equivalent and antimicrobial activities were determined by agar well diffusion method. It was observed that Q. incana Roxb. showed significant antibacterial activity against Grampositive and Gram-negative bacteria. n-Butanol fraction showed maximum activity against Micrococcus leuteus with 19 mm zone of inhibition. n-Butanol fraction of Q. incana Roxb. showed immense antifungal activity against Aspergillus niger (32 mm ± 0.55) and A. flavus (28 mm ± 0.45). Similarly n-butanol fraction showed relatively good antioxidant activity with IC 50 value of 55.4 ± 0.21 µg/mL. The NO scavenging activity of ethyl acetate fraction (IC 50 = 23.21 ± 0.31 µg/mL) was fairly good compared to other fractions. The current study of Q. incana Roxb. suggests the presences of synergetic action of some biological active compounds that may be present in the leaves of medicinal plant. Further studies are needed to better characterize the important active constituents responsible for the antimicrobial, antioxidant and free radical scavenging activity.

Gene, 2015

Multiple Drug Resistant (MDR) bacteria are no more inhibited by the front line antibiotics due to... more Multiple Drug Resistant (MDR) bacteria are no more inhibited by the front line antibiotics due to extreme resistance. Methicillin Resistant Staphylococcus aureus (MRSA) is one of the MDR pathogens notorious for its widespread infection around the world. The high resistance acquired by MRSA needs a serious concern and efforts should be carried out for the discovery of better therapeutics. With this aim, we designed a comparison of the metabolic pathways of the pathogen, MRSA strain 252 (MRSA252) with the human host (i.e., Homo sapiens) by using well-established in silico methods. We identified several metabolic pathways unique to MRSA (i.e., absent in the human host). Furthermore, a subtractive genomics analysis approach was applied for retrieval of proteins only from the unique metabolic pathways. Subsequently, proteins of unique MRSA pathways were compared with the host proteins. As a result, we have shortlisted few unique and essential proteins that could act as drug targets against MRSA. We further assessed the druggability potential of the shortlisted targets by comparing them with the DrugBank Database (DBD). The identified drug targets could be useful for an effective drug discovery phase. We also searched the sequences of unique as well as essential enzymes from MRSA in Protein Data Bank (PDB). We shortlisted at least 12 enzymes for which there was no corresponding deposition in PDB, reflecting that their crystal structures are yet to be solved! We selected Glutamate synthase out of those 12 enzymes owing to its participation in significant metabolic pathways of the pathogen e.g., Alanine, Aspartate, Glutamate and Nitrogen metabolism and its evident suitability as drug target among other MDR bacteria e.g., Mycobacteria. Due to the unavailability of any crystal structure of Glutamate synthase in PDB, we generated the 3D structure by homology modeling. The modeled structure was validated by multiple analysis tools. The active site of Glutamate synthase was identified by not only superimposing the template structure (PDB ID: 1E0A) over each other but also by the Parallel-ProBiS algorithm. The identified active site was further validated by crossdocking the co-crystallized ligand (2-oxoglutaric acid; AKG) of PDB ID: 1LLW. It was concluded that the comparative metabolic in silico analysis together with structure-based methods provides an effective approach for the identification of novel antibiotic targets against MRSA.

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets, 2011

Molecular Informatics, 2011

Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKMtub ) is an established drug... more Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKMtub ) is an established drug target against tuberculosis. The enzyme TMPKMtub is responsible for the survival of bacterium MTB and required to synthesize an essential building block of the bacterial DNA which is thymidine triphosphate (TTP). There are several potent inhibitors available against the target enzyme but the majority are substrate analogues. Recently, three dimensional structures of the enzyme TMPKMtub inhibitor complexes were resolved using X-ray crystallography. These available crystal structures were the basis of initiating a structure based lead identification campaign against TMPKMtub . The available information was utilized to perform structure-based virtual screening against TMPKMtub with the hope to diversify the structures of the current inhibitors. In order to setup the protocol, 10 000 out of 45 000 drug-like molecules were randomly selected from National Cancer Institute&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s (NCI) database. Additionally 105 known inhibitors along with 11 natural substrates were mixed with the 10 000 selected compounds. For the current study, a rigid based docking algorithm, i.e., FRED has been utilized to set up an efficient docking and scoring protocol. The methods including enrichment curves, consensus scoring and ROC curves are providing useful insights into the setting up of a suitable structure-based docking protocol against TMPKMtub . As a result, an optimum docking and scoring function has been identified for future large scale virtual screening. In the present work, we have demonstrated a rational choice of protocol for structure based virtual screening of chemical libraries and help to understand the influence of receptor flexibility by using multiple geometries.

Molecular Biology Reports, 2014

Methicillin resistant Staphylococcus aureus (MRSA) is one of the challenging bacterial pathogen d... more Methicillin resistant Staphylococcus aureus (MRSA) is one of the challenging bacterial pathogen due to its acquired resistance to the β lactam antibiotics. The Sortase A is an enzyme of Gram-positive bacteria including S. aureus to anchor surface proteins to the cell wall. Sortase A is well studied enzyme and considered as the drug target against MRSA. Sortase A plays active role in anchoring the virulence proteins on the cell wall of the Gram-positive bacteria. The inhibition of Sortase A activity results in the separation of S. aureus from the host cells and ultimately alleviation of the infection. Here, we adapted a structure-based virtual screening protocol which helped in identification of novel potential inhibitors of Sortase A. The protocol involved the docking of a chemical library of druglike compounds with the Sortase A binding site represented by multiple crystal structures. The compounds were ranked by multiple scoring functions and shortlisted for future experimental screening. The method resulted in shortlisting of three compounds as potential novel inhibitors of Sortase A out of a large chemical library. The high rankings of shortlisted compounds estimated by multiple scoring functions showed their binding potential with Sortase A. The results are proved to be a simple yet efficient choice of structure-based virtual screening. The identified compounds are druglike and show high rankings among all set protocols of the virtual screening. We hope that the study would eventually help to expedite the discovery of novel drug candidates against MRSA.

Medicinal Chemistry Research, 2013

Medicinal Chemistry Research, 2011

Journal of chemical information and modeling, 2008

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constru... more Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of structurally related steroidal alkaloids as butyrylcholinesterase (BuChE) inhibitors. Docking studies were employed to position the inhibitors into the BuChE active site to determine the most probable binding mode. The strategy was to explore multiple inhibitor conformations in producing a more reliable 3D-QSAR model. These multiple conformations were derived using the FlexS program. The conformation selection step for CoMFA was done by genetic algorithm. The genetic algorithm based CoMFA approach was found to be the best. Both CoMFA and CoMSIA yielded significant cross-validated q(2) values of 0.701 and 0.627 and the r(2) values of 0.979 and 0.982, respectively. These statistically significant models were validated by a test set of five compounds. Co...

Journal of molecular graphics & modelling, 2010

Acetylcholinesterase (AChE) plays a crucial role in nerve impulse transmission at cholinergic syn... more Acetylcholinesterase (AChE) plays a crucial role in nerve impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). AChE has become an important drug target because partial inhibition of AChE results in modest increase in ACh levels that can have therapeutic benefits, thus AChE inhibitors have proved useful in the symptomatic treatment of Alzheimer's disease. To establish an effective docking protocol for virtual screening of AChE, a comparative molecular docking study was performed. For this purpose six docking/scoring approaches (AutoDock, FlexX, MOE, Surflex-Dock, GOLD and FRED) were compared to determine their ability to reproduce the binding poses in twenty six complexes of AChE. Docking accuracy was evaluated by calculating the RMSD of the docked complexes. FRED was found to be the best in reproducing the experimental pose by placing it near the top of its ranking. The performance of scoring functions was evaluated by id...

Journal of molecular modeling, 2011

Structure-based 3D-QSAR approaches (CoMFA and CoMSIA) were applied to understand the structural r... more Structure-based 3D-QSAR approaches (CoMFA and CoMSIA) were applied to understand the structural requirements of the Cyclin-dependent kinase 5/p25 inhibitors. Cyclin-dependent kinase 5 (CDK5) is believed to play an important role in the development of the central nervous system during the process of mammalian embryogenesis. Genetic algorithm based docking program (GOLD) was successfully utilized to orient the compounds inside the binding pocket of the CDK5/p25 structure. The adapted alignment method with the suitable parameters resulted in a reliable model. Furthermore, the final model was robust enough to forecast the activities of test compounds, satisfactorily. The contour maps were produced around the functional groups to understand the SAR requirements. Moreover, we also investigate the structural attributes of the inhibitors which make them selective toward CDK5/p25 over its close counterpart, i.e., CDK2. The study could be helpful to rationalize the new compounds with better i...

European Journal of Medicinal Chemistry, 2010

New series of 4,5-disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (8a-j) and 2,5-disubstitu... more New series of 4,5-disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (8a-j) and 2,5-disubstituted-1,3,4-thiadiazoles (9a-h) were synthesized by dehydrative cyclization of hydrazinecarbothioamide derivatives (7a-k) by refluxing in 4N aqueous sodium hydroxide and by overnight stirring with polyphosphoric acid, respectively. The structures of the newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectroscopic studies and the synthesized compounds were screened for their antioxidant and urease inhibition activities. N-(2,4-Dimethylphenyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (9h) showed excellent antioxidant activity more than the standard drug whereas 4-(2,4-dimethylphenyl)-5-(3-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (8d) and 4-(2,3-dimethylphenyl)-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (8e) exhibited potent urease inhibitory activities.

Chemical Biology & Drug Design, 2011

Diaryl acylsulfonamide derivatives were reported as Human Umbilical Vein Endothelial cell (HUVEC)... more Diaryl acylsulfonamide derivatives were reported as Human Umbilical Vein Endothelial cell (HUVEC) inhibitors, stimulated by Vascular Endothelial Growth Factor (VEGF). VEGF has angiogenic property to cause colorectal cancer. A ligand-based 3D-QSAR technique was carried out on diaryl acylsulfonamide derivatives by using Comparative Molecular Field Analysis (CoMFA) studies to find relations between biological activities of inhibitors and their structures. In absence of binding mechanism for the ligand with VEGF receptor, current study hopes to shed some light on the inhibition mechanism of the ligands with HUVEC. 3D-QSAR technique was applied to a set of fifty ligands in order to facilitate the design of more potent inhibitors. However, the maximum cross-validated correlation coefficient value was found to be 0.417. The value is relatively low when compared to the usual acceptable cross-validated correlation coefficient, but no further improvements were observed by applying different available options. Therefore, the final model was used for further analysis. Additionally, the resulted CoMFA model was validated by an external set of 10 compounds yielding surprisingly, a satisfactory correlation coefficient value (r 2 pred) 0.80. Moreover, the analysis of the individual generated 3D contours helped in understanding the possible structural modifications of molecules to improve the inhibitory potency.