Download MendeleyUltra-large library docking for discovering new chemotypes.
Lyu, J., Wang, S., Balius, T.E., Singh, I., Levit, A., Moroz, Y.S., O'Meara, M.J., Che, T., Algaa, E., Tolmachova, K., Tolmachev, A.A., Shoichet, B.K., Roth, B.L., Irwin, J.J.(2019) Nature 566: 224-229
- PubMed: 30728502
- DOI: https://doi.org/10.1038/s41586-019-0917-9
- Primary Citation of Related Structures:
6DPT, 6DPX, 6DPY, 6DPZ - PubMed Abstract:
Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170?million make-on-demand compounds from 130?well-characterized reactions. The resulting library is diverse, representing over 10.7?million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC ¦Â-lactamase?(AmpC) and the D 4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D 4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which?revealed a?group of inhibitors without?known precedent.?This molecule?was optimized to 77?nM, which?places it?among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D 4 dopamine receptor, hit rates fell almost?monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000?ligands for the D 4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D 4 dopamine receptor.
Organizational Affiliation:
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
