Dynamic solution structure of streptomycin in Bioorganic & Medicinal Chemistry
Manchester, UK, July 17 2013 – C4X Discovery (C4XD), a leader in conformational drug discovery and design, announces the publication of a seminal paper describing the use of its novel NMR-based technology to determine the dynamic 3D structures of ligand molecules in solution. The publication in Bioorganic & Medicinal Chemistry1 is the first peer-reviewed description of the technology and demonstrates its potential value in drug discovery and development.
In the study, C4XD's technology was used to quantify the range of 3D conformations that the antibiotic streptomycin occupies in solution, which reveals that its preferred conformation is the same as its shape when bound to its target (i.e., its 'bioactive' conformation). Knowledge of the bioactive conformation is crucial in driving rational drug design and, until now, X-ray co-crystallography has been the only method that can routinely measure it. The results demonstrate that C4XD's technology reveals the bioactive conformation via a much-needed alternative route which, in contrast to X-ray co-crystallography, takes only a few weeks and works for all target classes.
C4XD has applied its technology to a wide range of ligands including peptides, carbohydrates, co-factors and small molecule drugs. In every case, its dynamic 3D structures capture the bioactive conformation. This has powerful implications for drug discovery, significantly accelerating the design of improved molecules during the hit discovery, hit-to-lead and lead optimisation processes.
In its in-house programmes, C4X Discovery has used the technology to identify hits and leads against high-value targets that are intractable to co-crystallography, including GPCRs and ion channels. Moreover, for targets that are amenable to co-crystallography, C4XD's technology provides surprising insights into how to optimise 'druggable' metrics such as affinity, selectivity and ADMET properties.
Dr Sam Williams, CEO of C4X Discovery, said, 'The publication of this study brings an important validation of our innovative NMR technology and its utility in drug development. We believe our technology is an important complement to the discovery tools already used by the pharmaceutical and biotechnology industries, with the potential to be integrated across multiple R&D programmes.'
1Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation, Blundell CD, Packer MJ and Almond A, Bioorganic & Medicinal
Chemistry In Press, Accepted Manuscript. Available online July 3 2013. http://dx.doi.org/10.1016/j.bmc.2013.06.056