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

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