ArticleJournal of medicinal chemistry2016
Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.
Article in Journal of medicinal chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- 3-(Pyridine-3-ylmethylene)chroman-4-one and tetralone derivatives: synthesis,RSC medicinal chemistry · 2026Article
- Efficient synthesis, dual anti-tubercular and antioxidant activity of triazole-acetophenone derivatives: enhanced efficacyRSC advances · 2026Article
- Mass Spectrometry Proteomics: A Key to Faster Drug Discovery.Journal of medicinal chemistry · 2026Review
- Fragment-Based Development of Small Molecule Inhibitors TargetingJournal of medicinal chemistry · 2025Article
- Fragment-based drug discovery campaigns guided by native mass spectrometry.RSC medicinal chemistry · 2024Review
- Structure-Function Analysis of the EssentialInternational journal of molecular sciences · 2024Article
- Deletion of theFrontiers in microbiology · 2024Article
- E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology.Journal of medicinal chemistry · 2023Review
- Fragment-Based Drug Discovery against Mycobacteria: The Success and Challenges.International journal of molecular sciences · 2022Review
- 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).European journal of medicinal chemistry · 2022Article
- Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.ChemMedChem · 2021Article
- Roles for Structural Biology in the Discovery of Drugs and Agrochemicals Targeting Sterol 14α-Demethylases.Journal of fungi (Basel, Switzerland) · 2021Review
- Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis.Scientific reports · 2021Article
- Multiple drug binding modes in Mycobacterium tuberculosis CYP51B1.Journal of inorganic biochemistry · 2020Article
- Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?Applied microbiology and biotechnology · 2019Review
- Mycobacterial genomics and structural bioinformatics: opportunities and challenges in drug discovery.Emerging microbes & infections · 2019Review
- One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review.Molecules (Basel, Switzerland) · 2018Review
- Probing Ligand Exchange in the P450 Enzyme CYP121 from Mycobacterium tuberculosis: Dynamic Equilibrium of the Distal Heme Ligand as a Function of pH and Temperature.Journal of the American Chemical Society · 2017Article
- Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 fromThe Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
13 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.