摘要
BackgroundThe NIH Roadmap is designed to enable the rapid transformation of new scientific knowledge into tangible benefits for public health. The Molecular Libraries Initiative is one of the initial projects developed under the New Pathways to Discovery roadmap theme. The Molecular Libraries Screening Centers Network (MLSCN) offers the research community an opportunity to leverage biology and chemistry resources to identify small molecule probes for innovative or challenging targets with the potential for insight into biological pathways that affect public health.MethodsThe MLSCN performs high-throughput screening (HTS) of biochemical or cell-based assays solicited from the scientific community against a high-quality library of >150,000 compounds maintained in a shared repository, which is expanding up to 500,000 with unique compounds based on known biological targets, active ingredients of FDA-approved drugs, clinical candidates, chemically diverse compounds with SAR clusters of 3-5, and natural product scaffolds (all with >90 % purity, >10 mg, ± rule of 5, solubility >20 μg/mL, and most importantly, QCed). The network provides synthetic chemistry capabilities to optimize hits identified in the initial screening to produce chemical probes that can be used for in vitro studies to interrogate the targets or phenotypes studied in the assays.ResultsOver the past 2 years, the MLSCN has implemented a diverse array of HTS assays, developed the capacity to conduct nearly 100 assay campaigns per year against the library of 150,000 compounds, and generated more than 13 million data points in PubChem. The HTS screening data from the MLSCN assays, including functional and pharmacologic selectivity data, are deposited into an open access database, PubChem (http://pubchem.ncbi.nlm.nih.gov). The assays screened to date span a variety of target classes (e.g., GPCRs, ion channels, transporters, enzymes, kinases) and methods (protein–protein interactions, cell phenotypes, and model organisms) in understudied areas of disease. Chemical probes have been developed for a number of targets, including 1) voltage-dependent potassium channel beta subunit (Kvb) (SID 856002, commonly know as ebselen, EC50 = 25.8 μmol/L and cell permeable); 2) glucocerebrosidase (GC), (CID 4264637, IC50 = 75 nmol/L); 3) muscarinic receptor subtypes; 4) new estrogen receptor GPR30; and 5) sphingosine-1-phosphate receptor subtypes. Over time, the use of the shared library by the MLSCN should provide extensive biological annotation, generating a unique and rich dataset available in the public domain.ConclusionsThe MLSCN, along with PubChem and the MLSMR, offers a new dimension in research opportunities for pharmacologists, chemists and biologists in the academic and nonprofit sector. The sharing of small molecules, biological assays, and screening data with the larger scientific community represents a new public sector paradigm that promises to facilitate the understanding of basic biological mechanisms and shorten the timeline for drug development, with resulting benefits to public health, especially for rare and neglected disorders.