Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A thorough evaluation of some of the most advanced docking and scoring methods currently available is described, and guidelines for the choice of an appropriate protocol for docking and virtual screening are defined. The generation of a large and highly curated test set of pharmaceutically relevant protein-ligand complexes with known binding affinities is described, and three highly regarded docking programs (Glide, GOLD, and ICM) are evaluated on the same set with respect to their ability to reproduce crystallographic binding orientations. Glide correctly identified the crystallographic pose within 2.0 A in 61% of the cases, versus 48% for GOLD and 45% for ICM. In general Glide appears to perform most consistently with respect to diversity of binding sites and ligand flexibility, while the performance of ICM and GOLD is more binding site-dependent and it is significantly poorer when binding is predominantly driven by hydrophobic interactions. The results also show that energy minimization and reranking of the top N poses can be an effective means to overcome some of the limitations of a given docking function. The same docking programs are evaluated in conjunction with three different scoring functions for their ability to discriminate actives from inactives in virtual screening. The evaluation, performed on three different systems (HIV-1 protease, IMPDH, and p38 MAP kinase), confirms that the relative performance of different docking and scoring methods is to some extent binding site-dependent. GlideScore appears to be an effective scoring function for database screening, with consistent performance across several types of binding sites, while ChemScore appears to be most useful in sterically demanding sites since it is more forgiving of repulsive interactions. Energy minimization of docked poses can significantly improve the enrichments in systems with sterically demanding binding sites. Overall Glide appears to be a safe general choice for docking, while the choice of the best scoring tool remains to a larger extent system-dependent and should be evaluated on a case-by-case basis.
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PMID:A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. 1521 8

The ability to find novel bioactive scaffolds in compound similarity-based virtual screening experiments has been studied comparing Tanimoto-based, ranking-based, voting, and consensus scoring protocols. Ligand sets for seven well-known drug targets (CDK2, COX2, estrogen receptor, neuraminidase, HIV-1 protease, p38 MAP kinase, thrombin) have been assembled such that each ligand represents its own unique chemotype, thus ensuring that each similarity recognition event between ligands constitutes a scaffold hopping event. In a series of virtual screening studies involving 9969 MDDR compounds as negative controls it has been found that atom pair descriptors and 3D pharmacophore fingerprints combined with ranking, voting, and consensus scoring strategies perform well in finding novel bioactive scaffolds. In addition, often superior performance has been observed for similarity-based virtual screening compared to structure-based methods. This finding suggests that information about a target obtained from known bioactive ligands is as valuable as knowledge of the target structures for identifying novel bioactive scaffolds through virtual screening.
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PMID:Scaffold hopping through virtual screening using 2D and 3D similarity descriptors: ranking, voting, and consensus scoring. 1650 72