Ligand Efficiency Driven Design of New Inhibitors of <i>Mycobacterium tuberculosis</i> Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches

Villemagne, Baptiste; Flipo, Marion; Blondiaux, Nicolas; Crauste, Céline; Malaquin, Stéphanie; Leroux, Florence; Piveteau, Catherine; Villeret, Vincent; Brodin, Priscille; Villoutreix, Bruno O.; Spérandio, Olivier; Soror, Sameh H.; Wohlkonig, A.; Wintjens, René; Deprez, Benoı̂t; Baulard, Alain R.; Willand, Nicolas

doi:10.1021/jm500422b

Cited by 61 publications

(64 citation statements)

References 144 publications

(255 reference statements)

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“…Here, the challenge often lies in elaborating initial fragment hits (by growing, merging, or linking them) into larger compounds that maintain these highly productive interactions [108,109]. In our DARC screen against Mcl-1, we focused on compounds larger than traditional fragments: this led to initial hits with easily detectable activity, albeit at some expense of ligand efficiency.…”

Section: Discussionmentioning

confidence: 99%

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

et al. 2015

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Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by “traditional” drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead deployed at protein interaction sites. To address the need for novel inhibitors of important protein interactions, here we introduce an alternate docking strategy specifically designed for this regime. Our method, termed DARC (Docking Approach using Ray-Casting), matches the topography of a surface pocket “observed” from within the protein to the topography “observed” when viewing a potential ligand from the same vantage point. We applied DARC to carry out a virtual screen against the protein interaction site of human anti-apoptotic protein Mcl-1, and found that 4 of the top-scoring 21 compounds showed clear inhibition in a biochemical assay. The Ki values for these compounds ranged from 1.2 to 21 µM, and each had ligand efficiency comparable to promising small-molecule inhibitors of other protein-protein interactions. These hit compounds do not resemble the natural (protein) binding partner of Mcl-1, nor do they resemble any known inhibitors of Mcl-1. Our results thus demonstrate the utility of DARC for identifying novel inhibitors of protein-protein interactions.

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Section: Discussionmentioning

confidence: 99%

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

et al. 2015

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“…Using fragment‐based approach, Villemange et al. found out potent ligands of mycobacterial transcriptional regulator EthR, and one compound 262 displayed inhibitory activity with IC 50 of 0.55 μM . Thomas et al.…”

Section: Sulfonamidesmentioning

confidence: 99%

New structural classes of antituberculosis agents

Kumar

Patel

Jain

2017

Medicinal Research Reviews

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Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.

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“…1 The literature reported derivatives of carbazoles and thiazoles along with their anti-mycobacterial activities [11][12][13][14][15][16][17] . Fig.…”

Section: In-vitro Anti-mycobacterial Evaluationmentioning

confidence: 99%

Design and synthesis of novel carbazolo–thiazoles as potential anti-mycobacterial agents using a molecular hybridization approach

et al. 2014

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Various substituted carbazolo-thiazoles 6 (a-o) have been synthesized in good yields by molecular hybridization approach. These synthesized compounds were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H 37 Rv strain at National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA. Among the tested series, compound 6c (MIC = 21 µM) exhibited the most promising anti-mycobacterial activity. A brief structure activity relationship (SAR) studies revealed that electron donating groups (OCH 3 and OH) especially on the phenyl ring of thiazole motif exhibited positive correlation with antimycobacterial activity. In addition, they displayed low cytotoxicity against a mammalian Vero cell line using MTT assay, thereby providing a high therapeutic index. This study reveals the significance of molecular hybridization and the scope for the development of carbazole clubbed thiazole compounds as potential anti-mycobacterial agents.

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Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches

Cited by 61 publications

References 144 publications

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

New structural classes of antituberculosis agents

Design and synthesis of novel carbazolo–thiazoles as potential anti-mycobacterial agents using a molecular hybridization approach

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