Yelekçi, KemalBabandi, A.Anosike, C.A.Ezeanyika, L.U.S.Yelekçi, K.Uba, A.I.2023-10-192023-10-19202241995-7157https://hdl.handle.net/20.500.12469/4846The major obstacle in controlling malaria is the mosquito’s resistance to insecticides, including pyrethroids. The resistance is mainly due to the over-expression of detoxification enzymes such as cytochromes. Insecticides tolerance can be reduced by inhibitors of P450s involved in insecticide detoxification. Here, to design potential CYP6P3 inhibitors, a homology model of the enzyme was constructed using the crystal structure of retinoic acid-bound cyanobacterial CYP120A1 (PDB ID: 2VE3; Resolution: 2.1 Å). Molecular docking study and computational modeling were employed to determine the inhibitory potentials of some phytoligands isolated from Ficus sycomorus against Anopheles coluzzii modeled P450 isoforms, CYP6P3, implicated in resistance. Potential ligand optimization (LE) properties were analyzed using standard mathematical models. Compounds 5, 8,and 9 bound to the Heme iron of CYP6P3 within 3.14, 2.47 and 2.59 Å, respectively. Their respective binding energies were estimated to be-8.93,-10.44, and-12.56 Kcal/mol. To examine the stability of their binding mode, the resulting docking complexes of these compounds with CYP6P3 were subjected to 50 ns MD simulation. The compounds remained bound to the enzyme and Fe (Heme):O (Ligand) distance appeared to be maintained over time. The coordination of a strong ligand to the heme iron shifts the iron from the high-to the stable low-spin form and prevented oxygen from binding to the heme thereby inhibiting the catalytic activity. The LE index showed the high potential of these compounds (5 and 8) to provide a core fragment for optimization into potent P450 inhibitors. © 2022 DSR Publishers/The University of Jordan. All Rights Reserved.eninfo:eu-repo/semantics/closedAccessCYP6P3CYP6P3 inhibitorsHomology modelingMolecular dockingMolecular dynamics simulation ligand efficiencycytochrome P450glutamic acidironligandoxygenretinoic acidzincamino acid sequenceAnophelesAnopheles coluzziiArticlebinding affinitybinding siteblood brain barriercontrolled studycrystal structuredetoxificationDNA bindingenzyme active siteenzyme bindingFicushydrogen bondinhibition constantligand bindinglipophilicitymathematical modelmolecular dynamicsmolecular modelnonhumanpharmacophorequantitative structure activity relationsimulationthermodynamicsvalidation processX ray crystallographyArticle2582752152-s2.0-85133010734N/AQ3