Multiple-Ligand-Based Virtual Screening: Methods and Applications of the MTree Approach
- 20 September 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (21), 6575-6584
- https://doi.org/10.1021/jm050078w
Abstract
We present a novel approach for ligand-based virtual screening by combining query molecules into a multiple feature tree model called MTree. All molecules are described by the established feature tree descriptor, which is derived from a topological molecular graph. A new pairwise alignment algorithm leads to a consistent topological molecular alignment based on chemically reasonable matching of corresponding functional groups. These multiple feature tree models find application in ligand-based virtual screening to identify new lead structures for chemical optimization. Retrospective virtual screening with MTree models generated for angiotensin-converting enzyme and the α1a receptor on a large candidate database yielded enrichment factors up to 71 for the first 1% of the screened database. MTree models outperformed database searches using single feature trees in terms of hit rates and quality and additionally identified alternative molecular scaffolds not included in any of the query molecules. Furthermore, relevant molecular features, which are known to be important for affinity to the target, are identified by this new methodology.Keywords
This publication has 16 references indexed in Scilit:
- Molecular similarity: a key technique in molecular informaticsOrganic & Biomolecular Chemistry, 2004
- Novel technologies for virtual screeningDrug Discovery Today, 2004
- Crystal structure of the human angiotensin-converting enzyme–lisinopril complexNature, 2003
- Finding Largest Subtrees and Smallest SupertreesAlgorithmica, 1998
- α1-Adrenergic Receptor Subtype Determinants for 4-Piperidyl Oxazole AntagonistsBiochemistry, 1998
- Automated chemical hypothesis generation and database searching with Catalyst®Perspectives in Drug Discovery and Design, 1995
- 3D-QSAR of angiotensin-converting enzyme and thermolysin inhibitors: a comparison of CoMFA models based on deduced and experimentally determined active site geometriesJournal of the American Chemical Society, 1993
- Similarity searching in REACCS. A new tool for the synthetic chemistJournal of Chemical Information and Computer Sciences, 1990
- Simple Fast Algorithms for the Editing Distance between Trees and Related ProblemsSIAM Journal on Computing, 1989
- Recent developments in the design of angiotensin‐converting enzyme inhibitorsMedicinal Research Reviews, 1985