BUILDER v.2: improving the chemistry of a de novo design strategy.
Significant improvements have been made to the de novo drug design program BUILDER. The BUILDER strategy is to find molecule templates that bind tightly to 'hot spots' in the target receptor, and then generate bridges to join these templates. In this paper, the bridging algorithm has been further developed to improve the chemical sense and diversity of the bridges, as well as the robustness of the technique. The improved algorithm is then applied to rebuild known bridges in methotrexate and HIV protease. Finally, the entire BUILDER approach is tested by rebuilding methotrexate de novo.
Roe
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Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
Kuntz
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D000465:Algorithms; D001665:Binding Sites; D016208:Databases, Factual; D015195:Drug Design; D005069:Evaluation Studies as Topic; D017320:HIV Protease Inhibitors / Q000737:chemistry; D008727:Methotrexate / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D012984:Software; D013402:Sugar Alcohols / Q000737:chemistry; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry
D017320:HIV Protease Inhibitors; D013402:Sugar Alcohols; C065300:A 74704; D014633:Valine; D008727:Methotrexate