Computational studies on ligand design and mechanism of action in context of receptors and enzymes

Abstract

The present thesis is focused on ligand design and understanding the structural basis for the mechanistic action of various enzymes and receptors using computational methods. A popular anti-viral drug, favipiravir, has been authorised for treating SARS-CoV-2 in several countries, as it shows several benefits in terms of reducing damage and shortening treatment time. A recent breakthrough revealed that the mechanism of action of favipiravir involves the induction of C-to-U point mutations in RNA, instead of chain termination. However, the literature lacks information on the structural basis for the induction of these mutations. In this context, a part of this thesis employs molecular dynamics (MD) simulations to analyse the impact of favipiravir present in the template and primer strands of RNA on the replication by RNA-dependent RNA Polymerase (RdRp), the enzyme that replicates the viral RNA of SARS-CoV-2. Subsequently, quantum mechanical (QM) methods, along with MD simulations are employed to understand the energetic feasibility of the prevalent mechanism of cyclodipeptide synthase (CDPS) enzymes that synthesize cyclodipeptides and to identify the catalytically important residues of CDPS required for this mechanism to occur. Further, the binding and inhibition of sigma-1 receptors by specific endogenous peptides are analysed, where molecular docking and MD simulations help examine the structural and dynamic characteristics of the sigma-1 receptor after peptide binding. Finally, to achieve better and more effective drugs for tuberculosis, pyrazinone derivatives are designed, and the structural as well as dynamical effects are analysed after their binding to enoyl acyl carrier protein reductase and ribosomal S1 protein targets, by employing molecular docking and MD simulations. Overall, the present thesis is expected to provide significant structural insights into the mechanism of action of specific receptors and the inhibitory role of designed ligands on various enzymes. newline