An exclusive computational insight toward molecular mechanism of MMV007571, a multitarget inhibitor of <i>Plasmodium falciparum</i>
Creators: name: Rawat, Ravi
name: Saurabh M. Verma
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biophysics
subject: Biochemistry
subject: 29999 Physical Sciences not elsewhere classified
subject: FOS: Physical sciences
subject: FOS: Physical sciences
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Genetics
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences

description: 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 <i>Plasmodium falciparum</i> dihydroorotate dehydrogenase (<i>Pf</i>DHODH) 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 Q<sub>o</sub> site of cytochrome bc1 complex while only MMV007571 illustrated notable binding characterstics for <i>Pf</i>DHODH. Molecular Dynamics (MD) simulations when carried out for native-<i>Pf</i>DHODH, <i>Pf</i>DHODH-MMV007571 and <i>Pf</i>DHODH-Genz667348 models (100 ns each) demonstrated the role of inhibitors over the N-terminus domain which experienced conformational transition from an open state (22 Å) to closed state (16 Å) 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 <i>Plasmodium falciparum</i>. AbbreviationsÅAngstromACTsArtemisinin combination therapiescyt bc1cytochrome bc1 complexhhour(s)KKelvinµMmicromolarMMVMedicine for malaria ventureNLucNanoluciferasenMnanomolarNPPNew permeation pathwayPDBProtein data bank<i>Pf</i>DHODH<i>Plasmodium falciparum</i> dihydroorotate dehydrogenasePOPC1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholineRBCRed blood corpusclesRMSDRoot-mean-square deviationSPStandard precisionvdWvan der WaalsXPExtra precisionyDHODHYeast dihydroorotate dehydrogenase Angstrom Artemisinin combination therapies cytochrome bc1 complex hour(s) Kelvin micromolar Medicine for malaria venture Nanoluciferase nanomolar New permeation pathway Protein data bank <i>Plasmodium falciparum</i> dihydroorotate dehydrogenase 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine Red blood corpuscles Root-mean-square deviation Standard precision van der Waals Extra precision Yeast dihydroorotate dehydrogenase Communicated by Ramaswamy H. Sarma