High-throughput virtual screening approach involving pharmacophore mapping, ADME filtering, molecular docking and MM-GBSA to identify new dual target inhibitors of Pf DHODH and Pf Cytbc1 complex to combat drug resistant malaria
Ravi Rawat, Saurabh Manaswita Verma · Journal of Biomolecular Structure and Dynamics · 2020
Emerging cases of drug resistance against Artemisinin combination therapies which are the current and the last line of defense against malaria makes the situation very alarming. Due to the liability of single-target drugs to be more prone to drug resistance, the trend of development of dual or multi-target inhibitors is emerging. Recently, a malaria box molecule, MMV007571 which is a well known new permeability pathways inhibitor was investigated to be also multi-targeting Plasmodium falciparum dihydroorotate dehydrogenase and cytochrome bc1 complex. The aspiration behind this study was to use the information of its pharmacophoric features essential for binding as two of its new targets. In this regard, high throughput virtual screening involving pharmacophore mapping, ADME filtering, molecular docking, and MM-GBSA calculations were carried out. This approach has lead to the identification of two new hits namely DT00V1902 and DT00V1922 which binds with -37.85 and -24.65 kcal/mol of more stable ΔG Bind energy at two targets than the lead molecule, MMV007571. The screened compounds are indicated to be carry improvement in binding potential and pharmacokinetic characters as per in silico studies. The authors propose that DT00V1902 and DT00V1922 can be forwarded for experimental validation and clinical studies for antimalarial chemotherapy. Communicated by Ramaswamy H. Sarma.