Enhancing specificity and sensitivity of pharmacophore-based virtual screening by incorporating chemical and shape features--a case study of HIV protease inhibitors.

Virtual screening (VS), if applied appropriately, could significantly shorten the hit identification and hit-to-lead processes in drug discovery. Recently, the version of VS that is based upon similarity to a pharmacophore has received increased attention. This is due to two major factors:  first, the public availability of the ZINC1 conformational database has provided a large selection pool with high-quality and purchasable small molecules; second, new technology has enabled a more accurate and flexible definition of pharmacophore models coupled with an efficient search speed. The major goal of this study was to achieve improved specificity and sensitivity of pharmacophore-based VS by optimizing the variables used to generate conformations of small molecules and those used to construct pharmacophore models from known inhibitors or from inhibitor−protein complex structures. By using human immunodeficiency virus protease and its inhibitors (PIs) as a case study, the impact of the key variables, including ...