Dataset Information

Fragment Hits: What do They Look Like and How do They Bind?

ABSTRACT: A "fragment hit", a molecule of low molecular weight that has been validated to bind to a target protein, can be an effective chemical starting point for a drug discovery project. Our ability to find and progress fragment hits could potentially be improved by enhancing our understanding of their binding properties, which to date has largely been based on tacit knowledge and reports from individual projects. In the work reported here, we systematically analyzed the molecular and binding properties of fragment hits using 489 published protein-fragment complexes. We identified a number of notable features that these hits tend to have in common, including preferences in buried surface area upon binding, hydrogen bonding and other directional interactions with the protein targets, structural topology, functional-group occurrence, and degree of carbon saturation. In the future, taking account of these preferences in designing and selecting fragments to screen against protein targets may increase the chances of success in fragment screening campaigns.

SUBMITTER: Giordanetto F

PROVIDER: S-EPMC6466478 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Fragment Hits: What do They Look Like and How do They Bind?

Giordanetto Fabrizio F Jin Chentian C Willmore Lindsay L Feher Miklos M Shaw David E DE

Journal of medicinal chemistry 20190401 7

A "fragment hit", a molecule of low molecular weight that has been validated to bind to a target protein, can be an effective chemical starting point for a drug discovery project. Our ability to find and progress fragment hits could potentially be improved by enhancing our understanding of their binding properties, which to date has largely been based on tacit knowledge and reports from individual projects. In the work reported here, we systematically analyzed the molecular and binding propertie ...[more]

PMID: 30875465

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Project description:Reactive multi-target 'fragment drugs' represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small 'dirty' drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM pathogens. These hits will now be evaluated in animal models of mycobacterial infection to determine whether any of them can be moved forward as a new antimycobacterial fragment drug candidate.

Dataset Information

Fragment Hits: What do They Look Like and How do They Bind?

Publications

Fragment Hits: What do They Look Like and How do They Bind?

Similar Datasets

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