Functioning of drug-metabolizing microsomal cytochrome P450s: In silico probing of proteins suggests that the distal heme 'active site' pocket plays a relatively 'passive role' in some enzyme-substrate interactions

In Silico Pharmacology
Avanthika VenkatachalamKelath Murali Manoj

Abstract

The currently held mechanistic understanding of microsomal cytochrome P450s (CYPs) seeks that diverse drug molecules bind within the deep-seated distal heme pocket and subsequently react at the heme centre. To explain a bevy of experimental observations and meta-analyses, we indulge a hypothesis that involves a "diffusible radical mediated" mechanism. This new hypothesis posits that many substrates could also bind at alternate loci on/within the enzyme and be reacted without the pertinent moiety accessing a bonding proximity to the purported catalytic Fe-O enzyme intermediate. Through blind and heme-distal pocket centered dockings of various substrates and non-substrates (drug molecules of diverse sizes, classes, topographies etc.) of microsomal CYPs, we explored the possibility of access of substrates via the distal channels, its binding energies, docking orientations, distance of reactive moieties (or molecule per se) to/from the heme centre, etc. We investigated specific cases like- (a) large drug molecules as substrates, (b) classical marker drug substrates, (c) class of drugs as substrates (Sartans, Statins etc.), (d) substrate preferences between related and unrelated CYPs, (e) man-made site-directed mutants' and naturall...Continue Reading

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Citations

Jul 26, 2016·Frontiers in Pharmacology·Kelath Murali ManojAvanthika Venkatachalam
Nov 30, 2018·Journal of Biomolecular Structure & Dynamics·Kelath Murali ManojSurjith Ramasamy
Jan 22, 2020·Biomolecular Concepts·Kelath Murali Manoj
Mar 19, 2020·Biomolecular Concepts·Kelath Murali ManojKannan Pakshirajan
May 18, 2018·Dose-response : a Publication of International Hormesis Society·Abhinav ParasharKelath Murali Manoj
Oct 18, 2019·Archives of Biochemistry and Biophysics·Kelath Murali ManojNikolai Mikhailovich Bazhin
Jul 30, 2021·Journal of Biomolecular Structure & Dynamics·Kelath Murali ManojAfsal Manekkathodi
Dec 18, 2021·Cell Biology International·Kelath Murali ManojLaurent Jaeken

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Methods Mentioned

BETA
equilibrium dialysis
dissection
X-ray

Software Mentioned

MarvinSketch
SWISS
Pymol
CAVER
ProFit
MGL Tools
AutoDock
Chimera
MarvinView
MODEL

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