BRUTUS:  Optimization of a Grid-Based Similarity Function for Rigid-Body Molecular Superposition. 1. Alignment and Virtual Screening Applications

• Published in: Journal of medicinal chemistry Vol. 48; no. 12; pp. 4076 - 4086
• Main Authors: Tervo, Anu J, Rönkkö, Toni, Nyrönen, Tommi H, Poso, Antti
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16.06.2005
• Subjects: Algorithms; Biological and medical sciences; Computer Simulation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemistry; Databases, Factual; Drug Design; Enzyme Inhibitors - chemistry; HIV Reverse Transcriptase - chemistry; Matrix Metalloproteinase 8 - chemistry; Matrix Metalloproteinase Inhibitors; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pancreatic Elastase - antagonists & inhibitors; Pancreatic Elastase - chemistry; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - chemistry; Quantitative Structure-Activity Relationship; Reverse Transcriptase Inhibitors - chemistry; Rhinovirus - enzymology; Thermolysin - antagonists & inhibitors; Thermolysin - chemistry; Leukocyte elastase; Serine endopeptidases; Database query; Similarity; Enzyme; Cyclooxygenase 2; Enzyme inhibitor; Virtual screening; Metalloendopeptidases; Thermolysin; Algorithm; Modeling; Optimization; Peptidases; Structure activity relation; Molecular model; Force field method; Neutrophil collagenase; Hydrolases; Antiviral; Oxidoreductases; Protease inhibitor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049123a

We have developed a fast grid-based algorithm, BRUTUS, for rigid-body molecular superposition and similarity searching. BRUTUS aligns molecules using field information derived from charge distributions and van der Waals shapes of the compounds. Molecules can have similar biological properties if their charge distributions and shapes are similar, even though they have different chemical structures; that is, BRUTUS can identify compounds possessing similar properties, regardless of their structures. In this paper, we present two applications of BRUTUS. First, BRUTUS was used to superimpose five sets of inhibitors. Second, two sets of known inhibitors were searched from a database, and the results were analyzed using self-organizing maps. We demonstrate that BRUTUS is successful in superimposing compounds using molecular fields and, importantly, is fast and accurate enough for virtual screening of chemical databases using a standard personal computer. This fast and efficient molecular-field-based algorithm is applicable for virtual screening of structurally diverse, active molecules.