An exclusive computational insight toward molecular mechanism of MMV007571, a multitarget inhibitor of Plasmodium falciparum

Abstract

Abstract Recently, two Malaria Box molecules namely MMV007571 and MMV020439 well known inhibitors of New Permeability Pathway (NPP) function also showed a secondary phenotype of inhibition of enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) and cytochrome bc1 complex in metabolic profile assays. Intricacies of their binding at the newly identified targets was need of the hour which motivated us to study their binding using molecular docking and dynamics simulations approach. Interestingly, molecular docking results of both MMV007571 and MMV020439 showed good binding affinity toward the Qo site of cytochrome bc1 complex while only MMV007571 illustrated notable binding characterstics for PfDHODH. Molecular Dynamics (MD) simulations when carried out for native-PfDHODH, PfDHODH-MMV007571 and PfDHODH-Genz667348 models (100\u2009ns each) demonstrated the role of inhibitors over the N-terminus domain which experienced conformational transition from an open state (22\u2009Å) to closed state (16\u2009Å) in the protein-inhibitor models. Dynamics also indicated that the loop domain near cofactor flavin mononucleotide (FMN) attained more felxibility which further lead to its poor binding and may contribute to inhibition of the oxidation (catalytic) process. Moreover, the pharmacophoric features of MMV007571 was justified and may serve as a template for the design of novel series of more potent multitarget inhibitors against Plasmodium falciparum. AbbreviationsÅ AngstromACTs Artemisinin combination therapiescyt bc1 cytochrome bc1 complexh hour(s)K KelvinµM micromolarMMV Medicine for malaria ventureNLuc NanoluciferasenM nanomolarNPP New permeation pathwayPDB Protein data bankPfDHODH Plasmodium falciparum dihydroorotate dehydrogenasePOPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholineRBC Red blood corpusclesRMSD Root-mean-square deviationSP Standard precisionvdW van der WaalsXP Extra precisionyDHODH Yeast dihydroorotate dehydrogenase Communicated by Ramaswamy H. Sarma