Molecular Modeling Evaluation of the Antimalarial Activity of Artemisinin Analogues: Molecular Docking and Rescoring using Prime/MM-GBSA Approach

Abstract

Artemisinin, a class of sesquiterpene endoperoxide, has been the objective of numerous studies to prepare better and safer anti-malarial drugs. A library of artemisinin analogues has been designed consisting of 144 analogues. The combined approaches of docking-molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model showed that artemisinin and its structural derivatives approach haem by pointing O1 and O2 at the endoperoxide linkage toward the iron center, a mechanism that is controlled by steric hindrance. A linear correlation was observed between the O-Fe distance and Glide score and binding free energy w ith correlation coefficient (R2) of 0.658 and 0.707. Quantitative structure activity relationships were developed between the anti-malarial activity (pIC50) of these compounds and molecular descriptors like docking score and binding free energy. Using Glide score and binding free energy the R2 were found in the range of 0.763 to 0.734 and 0.718 to 0.786 indicating that the predictive capabilities of the models were acceptable. Low level of root means square error for the majority of inhibitors which establish the docking and prime/MM-GBSA based prediction model as an efficient tool for generating more potent and specific inhibitors of haem by testing rationally designed lead compounds based on artemisinin derivatives.