Insilico design of peptide inhibitors against Cerebral Malaria

Abstract

Malaria, the mosquito-borne disease, is one of the toughest global health crises we face today. In 2018, it was responsible for 228 million infections and 405,000 deaths worldwide, with children alone accounting for 67% of the total deaths. As of today, Artemisinin Combination Therapy (ACT) is the most potent anti-malarial drug, but there is growing evidence for malarial parasites attaining Artemisinin resistance worldwide, potentially making malaria untreatable in the years to come. In this project, we computationally design a library of peptide drugs against Plasmodium falciparum, particularly targeting the interaction of the DBLb domain of erythrocyte membrane protein, PF110521 with the Human Endothelial receptor, Intercellular Adhesion Modelcule-1 (ICAM-1). We mine the RCSB Database to identify host-protein interactions, perform computational saturated mutagenesis on the chosen malarial proteins to identify epitopes responsible for strong binding and test these predictions using Molecular Dynamics simulations. The designed peptide inhibitors were then grafted in loop 6 of Cyclotide kalata B1, a circular plant protein known for its stability, anti-peptidase activity, and utility as an efficient drug scaffold. Finally, we identify essential peptide drugs that have the most stable interaction and potential anti-malarial activity.