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Molecular Docking and Optimization potentials of some phytoligands from Ficus sycomorus Fraction inhibiting Anopheles coluzzii Cytochrome CYP6P3 enzyme

Molecular Docking and Optimization potentials of some phytoligands from Ficus sycomorus Fraction inhibiting Anopheles coluzzii Cytochrome CYP6P3 enzyme

Abba Babandi, Chioma A Anosike, Abdullahi I Uba and Lawrance U.S Ezeayinka

A major obstacle in controlling malaria is mosquito’s resistance to insecticides, including pyrethroids. The resistance is mainly due to over-expression of detoxification enzymes such as Cytochrome P450. Insecticides tolerance can be reduced by inhibitors of P450s involved in insecticide detoxification. The ligand efficiency (LE) indexes were used as criteria in drug discovery and development decisions especially in fragment-based drug design (FBDD) perspective for efficient fragments optimization. Molecular docking study and computational modeling were employed using Glide XP software to determine the inhibitory potentials of some phytoligands isolated from Ficus sycomorus against Anopheles coluzzii P450 isoforms, CYP6P3, implicated in resistance. Homology model of the P450 enzyme was constructed using the Crystal structure of retinoic acid bound cyano bacterial CYP120A1 (PDB ID: 2VE3; Resolution: 2.1 Å). Potential LE and properties for optimization into formidable P450s inhibitors were analyzed using standard mathematical models. Compounds 5, 8 and 9 bound to the Heme iron of CYP6P3 at a distance of 3.14 Å, 2.47 Å and 2.59Å respectively, showing potential site of metabolism. The binding energies were 8.93, 10.44 and 12.56 Kcal/mol respectively showing non spontaneous interaction with the enzyme active site. The most common amino acid residues in the binding pocket were hydrophobic Phe123, Val310, Pro379 and Val380. These inhibitors were probably act by reversibly coordinating with the prosthetic heme iron atom and formation of quasi-irreversible complexes with the iron of the heme prosthetic group. 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 binding to the heme. This change in the spin state occurs concomitantly with a change in the redox potential of the P450s, which eventually inhibit the catalytic activities. The LE index showed high potential of these compounds to form core fragment for optimization into a potent P450s inhibitors.