Repurposing of Drug Bank Compounds against Plasmodium falciparum Dihydroorotate Dehydrogenase as novel anti malarial drug candidates by Computational approaches.

Abstract

This study aimed to repurpose Drug Bank Compounds against P. falciparum Dihydroorotate dehydrogenase (Pf-DHODH)a potential molecular target for antimalarial drug development due to its vital role in P. falciparum survival. Initially, the MATGEN server was used to screen drugs against Pf-DHODH (PDB ID 6GJG), followed by revalidating the results through docking by Autodock Vina through PyRx. Based on the docking results, three drugs namely, Talnifumate, Sulfaphenazole, and (3S)-N-[(2S)-1-[2-(1H-indol-3-yl)ethylamino]-1-oxopropan-2-yl]-1-(4-methoxyphenyl)-5-oxopyrrolidine-3-carboxamide-were subjected to molecular dynamics simulation for 100 ns. Molecular dynamics simulation results indicate that (3S)-N-[(2S)-1-[2-(1H-indol-3-yl)ethylamino]-1-oxopropan-2-yl]-1-(4-methoxyphenyl)-5-oxopyrrolidine-3-carboxamide- and Sulfaphenazole may target Pf-DHODH by forming a stable protein-ligand complex as they showed better free binding energy -130.58 kJ/mol, and -79.84 kJ/mol, respectively as compared to the free binding energy 116.255 kJ/mol of the reference compound; 3,6-dimethyl- ~ {N}-[4-(trifluoromethyl)phenyl]-[1,2]oxazolo[5,4-d]pyrimidin-4-amine. Although the studied compounds are drugs, still we applied Lipinski's rules and ADMET analysis that reconfirmed that these drugs have favorable drug-like properties. In conclusion, the results of the study show that Talniflumate and Sulfaphenazole may be potential antimalarial drug candidates.The derivatives of these drugs could be designed and tested to develop better drugs against Plasmodium species.

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