In silico screening of chloroquine analogues for compounds with more affinity for the Plasmodium falciparum chloroquine transporter as potential antimalarial drugs

Abstract

Background: Malaria is an acute febrile illness affecting over 229 million people worldwide. Children aged five years and below are affected the most, with the highest prevalence in Sub-Saharan Africa. Chloroquine was previously used as the first-line treatment for malaria due to its affordability and high efficacy, but resistance has developed. Resistance to chloroquine is due to a mutation in the protein Plasmodium falciparum Chloroquine Transporter (pfCRT) which effluxes the drug from the parasitic digestive vacuole, decreasing the drug concentration. Resistance has however been shown to be reversible by compounds that can bind to the protein. Methods: In silico screening for chloroquine analogues was done using SwissSimilarity, SWISSADME, SwissTargetPrediction, Pubchem sketcher, Chimera and Avogadro tools to predict pharmacodynamics and pharmacokinetic profiles of the selected analogues. Results: About 20 compounds with a similarity index of > 95% were obtained from the ZINC database. In total, 12 of the 20 compounds showed a higher binding affinity to the mutant pfCRT protein. Overall, four of the 12 had a binding affinity less than -8.0 compared to -7.0 for chloroquine. Compound ZINC01596768 had the greatest binding strength at -8.3. The other analogues were ZINC38050614, ZINC38050617, and ZINC38050615 with binding interaction strengths of -8.0, -8.2 and -8.2 respectively. Pharmacokinetic profile prediction showed all 12 compounds inhibited the enzymes CYP1A2 and CYP2D6, followed the Lipinski rules, had a high GI absorption, were permeant to the blood brain barrier, had no alerts on the PAINS criteria and had violated the rule of XLOGP3 > 3.5 in lead likeness. Compounds ZINC38050614, ZINC38050617, and ZINC38050615 were predicted to be substrates of P-glycoprotein. The synthetic accessibility score for the twelve compounds were below 3.07. Conclusions: Results demonstrated that the compounds ZINC01596768, ZINC38050614, ZINC38050617, and ZINC38050615 were potential candidates that could be tested and developed as co-formulations of chloroquine.