Faculty Publications

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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.
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.
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.

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