Venugopal, P.P.Das, B.K.Soorya, E.Chakraborty, D.2026-02-052020Proteins: Structure, Function and Genetics, 2020, 88, 2, pp. 327-3448873585https://doi.org/10.1002/prot.25807https://idr.nitk.ac.in/handle/123456789/24080G-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.beta alanineG protein coupled glucagon receptor inhibitorprotein inhibitorunclassified drugalanineamino acidG protein coupled receptorglucagon receptorligandprotein bindingallosterismantagonist potencyArticlebinding sitecrystal structuredensity functional theorydrug stabilityelectronhumanhydrogen bondhydrophobicityligand bindingmolecular dockingmolecular dynamicsnon insulin dependent diabetes mellituspredictionpriority journalsolvationthermodynamicsthree dimensional quantitative structure activity relationshipchemical phenomenachemistryenzyme active sitemetabolismquantitative structure activity relationAlanineAmino AcidsBinding SitesCatalytic DomainHumansHydrogen BondingHydrophobic and Hydrophilic InteractionsLigandsMolecular Docking SimulationMolecular Dynamics SimulationProtein BindingQuantitative Structure-Activity RelationshipReceptors, G-Protein-CoupledReceptors, GlucagonThermodynamics