Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2016 Jul 20

PMID 27432475

Citations 8

Authors

Madeline E Kavanagh

Janine L Gray

Sophie H Gilbert

Anthony G Coyne

Kirsty J McLean

Holly J Davis

Andrew W Munro

Chris Abell

Affiliations

Soon will be listed here.

Abstract

The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors' binding mode provides insight into the effect of weak nitrogen-donor ligands on the P450 heme, an improved understanding of factors governing CYP121-ligand recognition and speculation into the biological role of the enzyme for Mtb.

Citing Articles

Structure-Function Analysis of the Essential P450 Drug Target, CYP121A1.

Padayachee T, Lamb D, Nelson D, Syed K Int J Mol Sci. 2024; 25(9).

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Synthesis, biological evaluation and computational studies of pyrazole derivatives as CYP121A1 inhibitors.

Alshabani L, Kumar A, Willcocks S, Srithiran G, Bhakta S, Estrada D RSC Med Chem. 2022; 13(11):1350-1360.

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A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen).

Frederickson M, Selvam I, Evangelopoulos D, McLean K, Katariya M, Tunnicliffe R Eur J Med Chem. 2022; 230:114105.

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Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.

Walter I, Adam S, Gentilini M, Kany A, Brengel C, Thomann A ChemMedChem. 2021; 16(18):2786-2801.

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Design and Synthesis of Imidazole and Triazole Pyrazoles as CYP121A1 Inhibitors.

Kishk S, McLean K, Sood S, Smith D, Evans J, Helal M ChemistryOpen. 2019; 8(7):995-1011.

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