International Journal of Molecular Sciences

Abstract

Rationale Cotton is one of the most popular African natural product and cotton seeds contain gossypol (GP) a binaphthyl disesquiterpene exhibiting antimalarial activity in low micromolar range against both chloroquine-sensitive and chloroquine-resistant strains as inhibitor of plasmodium falciparum Lactate Dehydrogenase (pfLDH). Toxicity of GP due to its aldehyde functional groups lowered the interest in the natural compound driving attention to its derivatives particularly those selective over human LDH. Unfortunately LDH – GP complex has never been released after several attempts and docking models were not sufficiently accurate to provide relevant structural information to design novel potent and selective GP analogues. In this project we start a study of “half” GP derivatives with known LDH inhibitory activity in order to create progressively a stable model of LDH – GP. Objectives The main objective of this work is to design new low nanomolar antimalarials inhibitors of plasmodium falciparum Lactate Dehydrogenase (LDH) with hydroxynaphthoic scaffold. To reach this we characterize the LDH – ligand interactions using computer-based molecular simulations. Methods A pfLDH – HNA complex has been carefully prepared from 3D X-rays crystal structure of pfLDH – TDA1 (1T26.pdb) for a training set of 12 HNAs with known activity to build a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. The structural information derived from the model served to design new nanomolar hydroxynaphthoic acid analogues. Results From Molecular Modeling investigations the agreement between free energy of complexation (∆∆Gcompl) and Ki (pKi = - 0.2913×∆∆Gcompl + 1.761; R2 = 0.87, R2CV = 0.86, F = 66.8,  = 0.31) attests that more than 87% of the variation of the inhibitory activity data of the HNAs can be explained on the basis of the ligand-receptor interactions with pfLDH. The newly designed analogues …. Conclusions The computational approach used here is helpful in targeted drug design, providing valuable information to reach the interaction model of HNA – pfLDH and subsequently gossypol – LDH for the design of selective gossylic antimalarial agents.