RESUMO
The Small Molecule Discovery Center (SMDC) at the University of California, San Francisco, works collaboratively with the scientific community to solve challenging problems in chemical biology and drug discovery. The SMDC includes a high throughput screening facility, medicinal chemistry, and research labs focused on fundamental problems in biochemistry and targeted drug delivery. Here, we outline our HTS program and provide examples of chemical tools developed through SMDC collaborations. We have an active research program in developing quantitative cell-based screens for primary cells and whole organisms; here, we describe whole-organism screens to find drugs against parasites that cause neglected tropical diseases. We are also very interested in target-based approaches for so-called "undruggable", protein classes and fragment-based lead discovery. This expertise has led to several pharmaceutical collaborations; additionally, the SMDC works with start-up companies to enable their early-stage research. The SMDC, located in the biotech-focused Mission Bay neighborhood in San Francisco, is a hub for innovative small-molecule discovery research at UCSF.
Assuntos
Antiparasitários/farmacologia , Descoberta de Drogas/organização & administração , Ensaios de Triagem em Larga Escala/métodos , Bibliotecas de Moléculas Pequenas , Universidades/organização & administração , Academias e Institutos/organização & administração , California , Química Farmacêutica/métodos , Comportamento Cooperativo , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Internet , Terapia de Alvo Molecular , Doenças Negligenciadas/tratamento farmacológico , Canais de Potássio de Domínios Poros em Tandem , Setor Privado , Pesquisa Translacional Biomédica/organização & administraçãoRESUMO
Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.