Cytochromes P450 are hem-containing monooxygenases which catalyse biosynthesis of many compounds playing an essential role in cellular functions as well as degradation of drugs and xenobiotics. Some P450s (e. g., human CYP19 and CYP17, fungal CYP51) are valid target proteins for some drugs. The others P450s are also interesting for pharmacology-related researches. Aiming to design new fluorescent inhibitor of P450s we have synthesised the azole-bearing conjugate of ciprofloxacin (CPF-bab-Z1). To estimate potential of the compound as a ligand for CYPs we performed high-throughput virtual screening (multiple docking calculations) for CPF-bab-Z1 and multiple known 3D structures of P450s. The best affinity for CPF-bab-Z1 (the smallest value of energy of binding is equal -12.5 kcal/mol) were found for protein with PDB code 5esh among 28 structures of CYP51. The calculated pose of CPF-bab-Z1 in the active site of the protein is characterised by cyclopropyl (but not azole) proximity to the heme iron of the CYP51. The data obtained demonstrate perspectives for in vitro investigations of CPF-bab-Z1 with P450s.
In silico analysis of “protein-ligand” complexes of human CYP7 enzymes with modified borondipyrrome-tene (BODIPY) and steroids, containing photo-activated crosslinking groups, wasperformed in order to identify structural peculiarities of their interaction. It was found that BODIPY molecules and DHEA derivative with diazirine group are able to bind tightly with human steroid-hydroxylases. Binding affinity is comparable with corresponding values for essential ligands of the enzymes. Binding mode of the modified steroid corresponds to the binding mode of essential CYP7 ligands, so formation of hydroxylated products is possible. It was found that presence of both diazirine and NBD groups in a molecule significantly increases affinity of the compound in case of CYP7A1 and, especially, CYP7B1. Amino acid residues, located in a close proximity with photo-activated groups were detected, that can form covalent adducts with them. The obtained results can shed light on the mechanism of interaction of the compounds with recombinant human CYP7 enzymes in vitro. The results can also be used for the identification of modified amino acids of the proteins that are formed under photoactivation of the compounds in vitro.
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