Design of Potential Antimalarial Molecules Using QSAR, Molecular Docking and Molecular Dynamics Techniques

Malaria is a serious and potentially fatal tropical disease caused by parasites of the genus Plasmodium, transmitted to humans by the bite of infected Anopheles mosquitoes. There has recently been a growing emergence of strains resistant to current treatments, and synthetic analogues of bestatin, its natural inhibitor, have been designed using the four-component Ugi reaction (Ugi-4C), which has great combinatorial capabilities, to combat them. The objective is to design new inhibitors for malaria treatment using the capabilities of the Ugi-4C reaction. For library construction, the RDKit library was used. The complete set was evaluated by molecular docking (with AutoDock Vina, using the AD4 scoring function) and quantitative structure–activity relationship (QSAR) models. The library was studied with MAIP QSAR. Molecular dynamics simulations of some ligands of 1 ns duration were performed using NAMD software. A library of 245 compounds was built. Taking into account the energies obtained from molecular docking and the QSAR score, 8 inhibitor candidates were selected. From the molecular dynamics simulations performed on the 8 candidates, a root-mean-square deviation (RMSD) between 1–3 Å and a root-mean-square fluctuation (RMSF) in the ranges of 1–3 Å were obtained. The selected inhibitors adopt conformations stabilized by interactions with key residues of the active site (His-496, Asp-581, and Gly-460) and by coordination with the zinc ion present in the enzyme target. The RMSD and RMSF values evidenced the formation of stable complexes and limited conformational fluctuation.