Exploring potential Plasmodium kinase inhibitors: a combined docking, MD and QSAR studies

Malaria is a disease caused mostly by Plasmodium falciparum, affects millions of people each year. The kinases are validated targets for malaria infection. In this study, we investigate for real and hypothetical compounds that can inhibit cyclic guanosine monophosphate (CGMP)-dependent protein kinase using molecular docking via combined similarity analysis, molecular dynamics simulations, quantitative structure activity relationship (QSAR). Using Tanimoto similarity scores, ∼8.4 million compounds were screened. Compounds that have at least 70% similarity are used in further analysis. These compounds are assessed by means of docking, MMBPSA, MMGBSA and ANI_LIE. Based on consensus of different free energy methods and docking we revealed two potential inhibitors that can be useful for treatment of malaria. Apart from screening of real compounds, we have also selected the 10 most plausible hypothetical compounds by performing QSAR. By QSAR proposed pharmacophores, we generated over 247 hypothetical compounds and among them 19 molecules with lower QSAR predicted IC50 values and high docking scores were selected for further analysis. We selected the top 10 inhibitor candidates and performed MD simulations for free energy calculations like the protocol applied for real compounds. According to the free energy calculations, we suggest 2 real (C₃₄H₂₉F₅N₈O₄S and C₃₀H₂₇F₂N₇O₂S₂, PubChem IDs: 140564801 and 89035196, respectively) and 2 hypothetical (C₂₃H₂₇FN₆O₂S, MOL3 and C₂₃H₂₅FN₆O₂S, MOL4) compounds that can be effective inhibitors against the protein kinase of Plasmodium falciparum.Communicated by Ramaswamy H. Sarma.