Understanding Interactions between a Potential Antimalarial 'MAL2-11B' and its Targets using In Silico Methods.

Abstract

Introduction: The 70 kDa heat shock proteins (Hsp70) are ubiquitous molecules that play central roles in protein homeostasis. Their nucleotide-binding domains (NBD) are associated with the J domains of 40 kDa co-chaperone 'HSP40' in performing their functions. Interruption of this interaction significantly impacts the critical ATPase activity of Hsp70s, making them dysfunctional.

Methods: MAL2-11B is a dihydropyrimidine derivative that blocks Hsp70-Hsp40 interaction and hence holds the potential to be used as a drug. This Hsp70 inhibitor is a structural analogue of MAL3-101 that has proven anti-cancer and antiparasitic activity. MAL2-11B is predicted to have better drug-likeness, solubility, and absorption properties than MAL3-101. In the present study, we have therefore explored the potential of MAL2-11B as an antimalarial by using in silico tools.

Results: Molecular docking of MAL2-11B with all Plasmodium falciparum Hsp70 (PfHsp70) proteins revealed its preferential affinity for two out of four homologs at the nucleotide-binding site. Detailed analysis of the docked complexes helped us to predict the kind of protein-inhibitor interactions and specific amino acid residues involved in binding.

Conclusion: After in vitro validation, these data may be used as the groundwork for the design and development of new inhibitors and drugs against malaria.