The development of resistant malaria and lethality of the disease demands the search for new therapeutic candidates. In this line-up, thiolactone was identified as the potential lead structure and subjected to hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Overall, the QSAR results shows that the LOO cross-validated q(2) values of HQSAR, CoMFA and CoMSIA models are 0.791, 0.737 and 0.753, respectively. According to HQSAR, the hydrogen bond donor and acceptor were found to play an important role in governing antimalarial activity of thiolactone derivatives. The fragment contribution map of HQSAR, and contour maps of CoMFA and CoMSIA showed the presence of an electronegative group at the fifth position, and a bulky group at the third and fourth positions of the thiolactone ring, positively contributing to antimalarial activity. Furthermore, molecular docking was performed to analyze the binding mode of newly designed thiolactones with the active site residues of pf KAS I/II. The prediction of newly designed thiolactone molecules based on QSAR and docking score are in good accordance with each other. Therefore the ligand-based QSAR models and target structure-based docking model developed in this study may be successfully utilized for the design of new antimalarial agents.
Keywords: CoMFA; CoMSIA; HQSAR; Plasmodium falciparum; docking; thiolactone.