A 23-residue peptide fragment that forms a part of the α-1 helix of the ACE2 peptidase domain, the recognition domain for SARS-CoV2 on the ACE2 receptor, holds the potential as a drug to block the viral receptor binding domain (RBD) from forming a complex with ACE2. The peptide has recently been shown to bind the viral RBD with good efficiency. Here, we present a detailed analysis of the energetics of binding of the peptide to the SARS-CoV2 RBD. We use equilibrium molecular dynamics simulation to study the dynamics of the complex. We perform end-state binding energy calculations to gain a residue-level insight into the binding process and use the information to incorporate point mutations into the peptide. We demonstrate using binding energy calculations that the peptide with certain point mutations, especially E17L, shows a stronger binding to the RBD as compared to the wild type peptide. We propose that the modified peptide will thus be more efficient in blocking RBD-ACE2 binding.

Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure−function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.