7NQO

Mycobacterium tuberculosis Cytochrome P450 CYP121 in complex with lead compound 21

Summary for 7NQO

• Entry DOI: 10.2210/pdb7nqo/pdb
• Descriptor: Mycocyclosin synthase, HEME C, 4-[4-[2-(5-bromanyl-1~{H}-indol-3-yl)ethyl]pyrimidin-2-yl]morpholine, ... (8 entities in total)
• Functional Keywords: mycobacterium tuberculosis, heme-binding, inhibitor, complex, metal binding protein
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 45715.72

Authors

Selvam, I.R. (deposition date: 2021-03-01, release date: 2022-02-02, Last modification date: 2024-01-31)

Primary citation

Frederickson, M.,Selvam, I.R.,Evangelopoulos, D.,McLean, K.J.,Katariya, M.M.,Tunnicliffe, R.B.,Campbell, B.,Kavanagh, M.E.,Charoensutthivarakul, S.,Blankley, R.T.,Levy, C.W.,de Carvalho, L.P.S.,Leys, D.,Munro, A.W.,Coyne, A.G.,Abell, C.
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).
Eur.J.Med.Chem., 230:114105-114105, 2022

PubMed Abstract: There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance to current antituberculars. Herein a novel strategy is described for hit generation against promising TB targets involving X-ray crystallographic screening in combination with phenotypic screening. This combined approach (XP Screen) affords both a validation of target engagement as well as determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb) championed as a validated drug discovery target. A focused screening set was synthesized and tested by such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less than twenty), many of which also showed pan-assay activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC 6.25 μM), a novel hit compound suitable as a starting point for a more involved hit to lead candidate medicinal chemistry campaign.

PubMed: 35065413
DOI: 10.1016/j.ejmech.2022.114105

Experimental method

X-RAY DIFFRACTION (1.6 Å)