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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 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 Plasmodium falciparum.
| Abbreviations | ||
| Å | = | Angstrom |
| ACTs | = | Artemisinin combination therapies |
| cyt bc1 | = | cytochrome bc1 complex |
| h | = | hour(s) |
| K | = | Kelvin |
| µM | = | micromolar |
| MMV | = | Medicine for malaria venture |
| NLuc | = | Nanoluciferase |
| nM | = | nanomolar |
| NPP | = | New permeation pathway |
| PDB | = | Protein data bank |
| PfDHODH | = | Plasmodium falciparum dihydroorotate dehydrogenase |
| POPC | = | 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine |
| RBC | = | Red blood corpuscles |
| RMSD | = | Root-mean-square deviation |
| SP | = | Standard precision |
| vdW | = | van der Waals |
| XP | = | Extra precision |
| yDHODH | = | Yeast dihydroorotate dehydrogenase |
Communicated by Ramaswamy H. Sarma
Acknowledgements
We acknowledge Birla Institute of Technology, Mesra and Regional Centre for Biotechnology, Faridabad for providing infrastructural facility. R. R. thank Dalchand, Regional Centre for Biotechnology, Faridabad for providing technical support.
Disclosure statement
No potential conflict of interest was reported by the authors.
Author contributions
The manuscript was written by Ravi Rawat. Both the authors have given approval to the final version of the manuscript. Correspondence and requests for materials should be addressed to S.M.V. (Email: [email protected]) or R.R. (Email: [email protected]).