Faculty Publications
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Item Computational insights into factor affecting the potency of diaryl sulfone analogs as Escherichia coli dihydropteroate synthase inhibitors(Elsevier Ltd, 2019) Das, B.K.; PV, P.; Chakraborty, D.Dihydropteroate synthase (DHPS) is an alluring target for designing novel drug candidates to prevent infections caused by pathogenic Escherichia coli strains. Diaryl Sulfone (SO) compounds are found to inhibit DHPS competitively with respect to the substrate pABA (p-aminobenzoate). The extra aromatic ring of diaryl sulfone compounds found to stabilize them in highly flexible pABA binding loops. In this present study, a statistically significant 3D-QSAR model was developed using a data set of diaryl sulfone compounds. The favourable and unfavourable contributions of substitutions in sulfone compounds were illustrated by contour plot obtained from the developed 3D-QSAR model. Molecular docking calculations were performed to investigate the putative binding mode of diaryl sulfone compounds at the catalytic pocket. DFT calculations were carried out using SCF approach, B3LYP- 6-31 G (d) basis set to compute the HOMO, LUMO energies and their respective location at pABA binding pocket. Further, the developed model was validated by FEP (Free Energy Perturbation) calculations. The calculated relative free energy of binding between the highly potent and less potent sulfone compound was found to be ?3.78 kcal/ mol which is comparable to the experimental value of ?5.85 kcal/mol. A 10 ns molecular dynamics simulation of inhibitor and DHPS confirmed its stability at pABA catalytic site. Outcomes of the present work provide deeper insight in designing novel drug candidates for pathogenic Escherichia coli strains. © 2018 Elsevier LtdItem Effect of hydrophobic and hydrogen bonding interactions on the potency of ß-alanine analogs of G-protein coupled glucagon receptor inhibitors(John Wiley and Sons Inc. P.O.Box 18667 Newark NJ 07191-8667, 2020) Venugopal, P.P.; Das, B.K.; Soorya, E.; Chakraborty, D.G-protein coupled glucagon receptors (GCGRs) play an important role in glucose homeostasis and pathophysiology of Type-II Diabetes Mellitus (T2DM). The allosteric pocket located at the trans-membrane domain of GCGR consists of hydrophobic (TM5) and hydrophilic (TM7) units. Hydrophobic interactions with the amino acid residues present at TM5, found to facilitate the favorable orientation of antagonist at GCGR allosteric pocket. A statistically robust and highly predictive 3D-QSAR model was developed using 58 ?-alanine based GCGR antagonists with significant variation in structure and potency profile. The correlation coefficient (R2) and cross-validation coefficient (Q2) of the developed model were found to be 0.9981 and 0.8253, respectively at the PLS factor of 8. The analysis of the favorable and unfavorable contribution of different structural features on the glucagon receptor antagonists was done by 3D-QSAR contour plots. Hydrophobic and hydrogen bonding interactions are found to be main dominating non-bonding interactions in docking studies. Presence of highest occupied molecular orbital (HOMO) in the polar part and lowest unoccupied molecular orbital (LUMO) in the hydrophobic part of antagonists leads to favorable protein-ligand interactions. Molecular mechanics/generalized born surface area (MM/GBSA) calculations showed that van der Waals and nonpolar solvation energy terms are crucial components for thermodynamically stable binding of the inhibitors. The binding free energy of highly potent compound was found to be ?63.475 kcal/mol; whereas the least active compound exhibited binding energy of ?41.097 kcal/mol. Further, five 100 ns molecular dynamics simulation (MD) simulations were done to confirm the stability of the inhibitor-receptor complex. Outcomes of the present study can serve as the basis for designing improved GCGR antagonists. © 2019 Wiley Periodicals, Inc.Item Epitope-Based Potential Vaccine Candidate for Humoral and Cell-Mediated Immunity to Combat Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic(American Chemical Society, 2020) Das, B.K.; Chakraborty, D.The emergence of severe acute respiratory syndrome from novel Coronavirus (SARS-CoV-2) has put an immense pressure worldwide where vaccination is believed to be an efficient way for developing hard immunity. Herein, we employ immunoinformatic tools to identify B-cell, T-cell epitopes associated with the spike protein of SARS-CoV-2, which is important for genome release. The results showed that the highly immunogenic epitopes located at the stalk part are mostly conserved compared to the receptor binding domain (RDB). Further, two vaccine candidates were computationally modeled from the linear B-cell, T-cell epitopes. Molecular docking reveals the crucial interactions of the vaccines with immune-receptors, and their stability is assessed by MD simulation studies. The chimeric vaccines showed remarkable binding affinity toward the immune cell receptors computed by the MM/PBSA method. van der Waals and electrostatic interactions are found to be the dominant factors for the stability of the complexes. The molecular-level interaction obtained from this study may provide deeper insight into the process of vaccine development against the pandemic of COVID-19. © 2020 American Chemical Society.Item Molecular mechanism of inhibition of COVID-19 main protease by ?-adrenoceptor agonists and adenosine deaminase inhibitors using in silico methods(Taylor and Francis Ltd., 2022) Venugopal, P.P.; Chakraborty, D.Novel coronavirus (COVID-19) responsible for viral pneumonia which emerged in late 2019 has badly affected the world. No clinically proven drugs are available yet as the targeted therapeutic agents for the treatment of this disease. The viral main protease which helps in replication and transcription inside the host can be an effective drug target. In the present study, we aimed to discover the potential of ?-adrenoceptor agonists and adenosine deaminase inhibitors which are used in asthma and cancer/inflammatory disorders, respectively, as repurposing drugs against protease inhibitor by ligand-based and structure-based virtual screening using COVID-19 protease-N3 complex. The AARRR pharmacophore model was used to screen a set of 22,621 molecules to obtain hits, which were subjected to high-throughput virtual screening. Extra precision docking identified four top-scored molecules such as +/?-fenoterol, FR236913 and FR230513 with lower binding energy from both categories. Docking identified three major hydrogen bonds with Gly143, Glu166 and Gln189 residues. 100 ns MD simulation was performed for four top-scored molecules to analyze the stability, molecular mechanism and energy requirements. MM/PBSA energy calculation suggested that van der Waals and electrostatic energy components are the main reasons for the stability of complexes. Water-mediated hydrogen bonds between protein-ligand and flexibility of the ligand are found to be responsible for providing extra stability to the complexes. The insights gained from this combinatorial approach can be used to design more potent and bio-available protease inhibitors against novel coronavirus. Communicated by Ramaswamy H. Sarma. © 2020 Informa UK Limited, trading as Taylor & Francis Group.Item Deciphering the competitive inhibition of dihydropteroate synthase by 8 marcaptoguanine analogs: enhanced potency in phenylsulfonyl fragments(Taylor and Francis Ltd., 2022) Das, B.K.; Chakraborty, D.The emergence of sulfa-drug resistance and reduced efficacy of pterin-based analogs towards Dihydropteroate synthase (DHPS) inhibition dictate a pressing need of developing novel antimicrobial agents for immune-compromised patients. Recently, a series of 8-Marcaptoguanin (8-MG) derivatives synthesized for 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (experimental KD ∼ 100–.0.36) showed remarkable homology with the pteroic-acid and serve as a template for product antagonism in DHPS. The present work integrates ligand-based drug discovery techniques with structure-based docking, enhanced MD simulation, and MM/PBSA techniques to demonstrate the essential features of 8-MG analogs which make it a potent inhibitor for DHPS. The delicate balance in hydrophilic, hydrophobic substitutions on the 8-MG core is the crucial signature for DHPS inhibition. It is found that the dynamic interactions of active compounds are mainly dominated by consistent hydrogen bonding network with Asp 96, Asn 115, Asp 185, Ser 222, Arg 255 and π-π stacking, π-cation interactions with Phe 190, Lys 221. Further, two new 8-MG compounds containing N-phenylacetamide (compound S1, ΔGbind-eff = –62.03 kJ/mol) and phenylsulfonyl (compound S3, ΔGbind-eff = −71.29 kJ/mol) fragments were found to be the most potent inhibitor of DHPS, which stabilize the flexible pABA binding loop, thereby increasing their binding affinity. MM/PBSA calculation shows electrostatic energy contribution to be the principal component in stabilizing the inhibitors in the binding pocket. This fact is further confirmed by the higher energy barrier obtained in umbrella sampling for this class of inhibitors. © 2021 Informa UK Limited, trading as Taylor & Francis Group.Item Influence of Ion Specificity and Concentration on the Conformational Transition of Intrinsically Disordered Sheep Prion Peptide(John Wiley and Sons Inc, 2022) Singh, O.; Kumar das, B.; Chakraborty, D.The structural sensitivity of the intrinsically disordered proteins with the ions has been observed experimentally; however, it is still unclear how the presence of different metal ions affects structural stability. We performed an atomistic molecular dynamics simulation of sheep prion peptide (142–167) in presence of different monovalent, divalent ions at various concentrations to find out the effect of the size, charge, and ionic concentration on the structure of the peptide. It is found that Li+ ions have a higher survival probability compared to Na+, K+, and Mg2+ affecting the solvation structure of the protein leading to the alpha-helix structure. At high concentration, due to the increase in the ion-solvent and counter-ion interactions, the effect of the ions is screened on the surface of the protein and hence no ion specificity is observed. This study demonstrates how ions can be used to regulate the protein structure and function that can help in designing drugs. © 2022 Wiley-VCH GmbH.Item Exploring the multiple conformational states of RNA genome through interhelical dynamics and network analysis(Elsevier Inc., 2022) Singh, O.; Venugopal, P.P.; Mathur, A.; Chakraborty, D.The structural variation of RNA is often very transient and can be easily missed in experiments. Molecular dynamics simulation studies along with network analysis can be an effective tool to identify prominent conformations of such dynamic biomolecular systems. Here we describe a method to effectively sample different RNA conformations at six different temperatures based on the changes in the interhelical orientations. This method gives the information about prominent states of the RNA as well as the probability of the existence of different conformations and their interconnections during the process of evolution. In the case of the SARS-CoV-2 genome, the change of prominent structures was found to be faster at 333 K as compared to higher temperatures due to the formation of the non-native base pairs. ΔΔG calculated between 288 K and 363 K are found to be 10.31 kcal/mol (88 nt) considering the contribution from the multiple states of the RNA which agrees well with the experimentally reported denaturation energy for E. coli α mRNA pseudoknot (∼16 kcal/mol, 112 nt) determined by calorimetry/UV hyperchromicity and human telomerase RNA telomerase (4.5–6.6 kcal/mol, 54 nt) determined by FRET analysis. © 2022 Elsevier Inc.Item Exploring the Barriers in the Aggregation of a Hexadecameric Human Prion Peptide through the Markov State Model(American Chemical Society, 2023) Das, B.K.; Singh, O.; Chakraborty, D.The prefibrillar aggregation kinetics of prion peptides are still an enigma. In this perspective, we employ atomistic molecular dynamics (MD) simulations of the shortest human prion peptide (HPP) (127GYMLGS132) at various temperatures and peptide concentrations and apply the Markov state model to determine the various intermediates and lag phases. Our results reveal that the natural mechanism of prion peptide self-assembly in the aqueous phase is impeded by two significant kinetic barriers with oligomer sizes of 6-9 and 12-13 peptides, respectively. The first one is the aggregation of unstructured lower-order oligomers, and the second is fibril nucleation, which impedes the further growth of prion aggregates. Among these two activation barriers, the second one is found to be dominant irrespective of the increase in temperature and peptide concentration. These lag phases are captured in all three different force-field parameters, namely, GROMOS-54a7, AMBER-99SB-ILDN, and CHARMMS 36m, at different concentrations. The GROMOS-54a7 and AMBER-99SB-ILDN force fields showed a comparatively higher percentage of β-sheet formation in the metastable aggregate that evolved during the aggregation process. In contrast, the CHARMM-36m force field showed mostly coil or turn conformations. The addition of a novel catecholamine derivative (naphthoquinone dopamine (NQDA)) arrests the aggregation process between the lag phases by increasing the activation barrier for the Lag1 and Lag2 phases in all of the force fields, which further validates the existence of these lag phases. The preferential binding of NQDA with the peptides increases the hydration of peptides and eventually disrupts the organized morphology of prefibrillar aggregates. It reduces the dimer dissociation energy by −24.34 kJ/mol. © 2023 American Chemical Society.Item Designing Reaction Coordinate for Ion-Induced Pore-Assisted Mechanism of Halide Ions Permeation through Lipid Bilayer by Umbrella Sampling(American Chemical Society, 2023) Mathath, A.V.; Das, B.K.; Chakraborty, D.Ion permeation mechanism through lipid membranes helps to understand cellular processes. We propose new reaction coordinates that allow ions to permeate according to their water affinity and interaction with the hydrophilic layer. Simulations were done for three different halides (F-, Cl-, and I-) in two different lipid bilayers, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dinervonoyl-sn-glycero-3-phosphocholine (DNPC). It is found that the involvement of the water molecules decreases the free energy barrier. The ions were found to follow different pathways for permeation. Formation of proper pores required a collaboration effort of the hydration shell water molecules and the hydrophilic lipid layer, which was favored in the case of Cl- ions. The optimum charge density and good water affinity of Cl- with respect to F- and I- ions helped to form the pore. The effect was prominently seen in the case of DNPC membrane because of its higher hydrophobic thickness. The umbrella sampling results were compared with other methods such as the Markov state model (MSM) and well-tempered metadynamics (WT-metaD). © 2023 American Chemical Society.Item Study of Correlated Motions to Detect the Conformational Transitions of the Intrinsically Disordered Sheep Prion Peptide(American Chemical Society, 2024) Chakraborty, D.; Singh, O.; Parameswaran, D.Intrinsically disordered proteins (IDPs) are known for their random structural changes throughout their sequence based on the environment. The mechanism underlying these structural changes is difficult to explain. All biological processes are known to follow the direction through which they act. A study of the correlated motion can help to understand the direction of the change. Herein, we introduced the multivariate statistical analysis (MSA) technique to study the correlated motion of the peptide. The correlated motion of the sheep prion peptide was studied with the change in the temperature and solvent. These techniques helped to identify the contributing residual motions that helped to form the different secondary structures of the protein and also the triggering factors that drive these sorts of residual motions. The structural details match the experimentally reported data. It was found that the direction of the change of the secondary structure for this peptide shifted from the C-terminal to the N-terminal with an increase in the temperature. It was found that the involvement of the hydrophobic residues present at the C-terminal and the middle residues (residues 12-17) is responsible for forming a β-sheet at the normal temperature. Hydration water was found to play an important role in this change. Insights gained from this study can be used to design strategies for desirable structural changes in the IDPs. © 2024 American Chemical Society.