Drug repurposing approach for potential Pfmrk inhibitors as antimalarial agents: an In-silico analysis

Abstract

Alteration of one or few amino acid residues can affect structure [1–3] and function [4] of a protein and, in extreme cases, be the difference between health and disease [5, 6]. Understanding structural consequences of point mutations is important for drug design [7, 8] and could also accelerate optimization of enzymatic function via directed evolution [9, 10]. In these and other applications, theoretical models [11] could be of immense help, provided they are sufficiently accurate. In this context, AlphaFold2 [12] has recently made breakthroughs in predicting global protein structure from sequence with unprecedented precision. Notwithstanding, it is not yet known whether AF is sensitive enough to detect small, local effects of single mutations. Even if AF achieves high accuracy, the effect of a mutation may be small compared to the inherent conformational dynamics of the protein – predicting static structures may not be particularly informative [13–15]. Furthermore, as accuracy improves, evaluating the quality of predictions becomes increasingly complicated by the inherent noise in experimental measurements [15–22].