Standard force field-based simulations to accomplish structure-based evaluations of lead molecules is a powerful tool. Combining protein fragmentation into tractable sub-systems with continuum solvation method is envisaged to enable quantum mechanics-based electronic structure calculations of macromolecules in their realistic environment. This along with incorporation of many-body polarization effect in molecular dynamics simulations may augment an accurate description of electrostatics of protein-inhibitor systems for effective drug design. Rheumatoid arthritis (RA) is a complex autoimmune disorder plagued by the ceiling effect of current targeted therapies, encouraging identification of new druggable targets and corresponding drug design to tackle the refractory form of disease. In this study, polarization-inclusive force field approach has been used to model protein solvation and ligand binding for 'Mitogen-activated protein kinase' (MAP3K8), a regulatory node of notable pharmacological relevance in RA synovial biology. For MAP3K8 inhibitors belonging to different scaffold series, the calculations illustrated differential electrostatic contribution to their relative binding affinities and successfully explained examples from available structure-activity relationship studies. Results from this study exemplified i) the advantage of this approach in reliably ranking inhibitors having close nanomolar range activities for the same target; and ii) its prospective application in lead molecule identification aiding drug discovery efforts in RA.Communicated by Ramaswamy H. Sarma.
Keywords: MD simulation; binding free energy; drug discovery; electrostatics; protein polarized charges; rheumatoid arthritis.