In silico and in vitro studies on interaction of novel non-imidazole histamine H₃R antagonists with CYP3A4.

ID: ALA4619729

Journal: Bioorg Med Chem Lett

Title: In silico and in vitro studies on interaction of novel non-imidazole histamine H₃R antagonists with CYP3A4.

Authors: Podlewska S, Latacz G, Łażewska D, Kieć-Kononowicz K, Handzlik J.

Abstract: The paper presents in silico study to explain differences in the influence of the series of non-imidazole histamine receptor H₃ ligands on the activity of cytochrome P-450 3A4 isoform, which was verified in in vitro tests. The compounds appeared to induce broad range of effects - from significant inhibition (-61% reduction of CYP3A4 control activity) to extreme activation (+713% of control activity). Structure-activity relationship for examined compounds was analyzed, with special attention paid to the influence of substituent and the chain length. Docking, molecular dynamics studies, and their statistical analysis allowed to identify those interactions that can be responsible for determination of particular activity type of a compound toward CYP3A4 (activation/inhibition). It resulted in indication of several amino acid residues, which should be carefully analyzed during estimation of compound effects on CYP3A4 activity.

CiteXplore: 32249114

DOI: 10.1016/j.bmcl.2020.127147

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