Repository logo
 

Publication:
Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors

Loading...
Thumbnail Image

Advisor

Coadvisor

Graduate program

Undergraduate course

Journal Title

Journal ISSN

Volume Title

Publisher

Type

Article

Access right

Acesso restrito

Abstract

The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 μM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development.

Description

Keywords

Language

English

Citation

Journal of Medicinal Chemistry, v. 59, n. 7, p. 3272-3302, 2016.

Related itens

Units

Unit
Faculdade de Ciências Farmacêuticas
FCF
Campus: Araraquara

Departments

Undergraduate courses

Graduate programs