Project Profile at Small Molecule Discovery Center (SMDC) at UCSF

Date: 30 December 2013


The Small Molecule Discovery Center (SMDC) at UCSF comprises more than twenty staff scientists, students, and postdocs engaged in lead discovery efforts spanning screening through lead optimization. The SMDC collaborates with researchers from academia and industry, with a particular emphasis on challenging drug targets and in orphan and neglected diseases. Two brief research summaries are provided to highlight some of the novel small molecules that have emerged from the SMDC and its collaborators in recent years. The first project involves the application of fragment-­‐based screening to identify novel chemical lead matter for a well-­‐validated drug target (beta-­‐lactamase). The second project sought to identify therapeutic leads for prion disease and involved phenotypic cell-­‐based screening and extensive medicinal chemistry to produce brain-­‐penetrant lead compounds.

The SMDC and Prof. Yu Chen (University of South Florida) have collaborated to identify the first nM-­‐affinity, non-­‐covalent inhibitors of the Class A beta-­‐lactamase CTX-­‐M, which inactivates third-­‐generation cephalosporins. Classical inhibitors like clavulanic acid react with the active-­‐site serine of beta-­‐lactamases to produce a stable acyl-­‐enzyme complex that inactivates the hydrolase. To identify novel lead matter for this important drug target, Dr. Chen conducted a fragment screen using computational docking approaches. Fragment hits were next evaluated for biochemical activity and further studied by X-­‐ray. Several X-­‐ray structures were solved and this revealed diverse molecular recognition events between the fragments and the protein. 1 These interactions included CH-­‐pi, hydrogen bonding, ionic, and hydrophobic interaction. Next a ‘fragment merging’ strategy was employed in which the recognition features of multiple fragments were combined in larger, lead-­‐sized molecules. The merged fragments were structurally characterized and further optimized by introducing and optimizing additional H-­‐bonding and hydrophobic contacts.2 This process ultimately produced analogs like SMDC-­‐753487 exhibiting Ki values up to 10,000-­‐fold improved over the original fragments (Figure). Importantly, optimized inhibitors like SMDC-­‐753487 were shown to reverse cephalosporin resistance in E. coli strains expressing CTX-­‐M beta-­‐lactamase, suggesting that reversible beta-­‐lactamase inhibition merits further study as a therapeutic strategy.

Source: Small Molecule Discovery Center at UCSF

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Contact Name: Adam Renslo

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