COSMOsim3D: 3D-Similarity and Alignment Based on COSMO Polarization Charge Densities

• Published in: Journal of chemical information and modeling Vol. 52; no. 8; pp. 2149 - 2156
• Main Authors: Thormann, Michael, Klamt, Andreas, Wichmann, Karin
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27.08.2012
• Subjects: Analytical chemistry; Binding sites; Biological and medical sciences; Cell metabolism, cell oxidation; Cell physiology; Databases, Pharmaceutical; Drug Design; Fundamental and applied biological sciences. Psychology; Interactions. Associations; Intermolecular phenomena; Isomerism; Ligands; Models, Molecular; Molecular and cellular biology; Molecular biophysics; Molecular Conformation; Molecules; Pharmacology; Quantum Theory; Reproducibility of Results; Simulation; T cell receptors; Validation; Ligand binding; Polarization; Histogram; Probabilistic approach; Quantum chemistry; Similarity; Ligand; Grid; Molecular interaction; Case based reasoning; Experimental study; Alignment; Discrimination; Database; Polarity; Metric; Biological receptor
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci300205p

COSMO σ-surfaces resulting from quantum chemical calculations of molecules in a simulated conductor, and their histograms, the so-called σ-profiles, are widely proven to provide a very suitable and almost complete basis for the description of molecular interactions in condensed systems. The COSMOsim method therefore introduced a global measure of molecular similarity on the basis of similarity of σ-profiles, but it had the disadvantage of neglecting the 3D distribution of molecular polarities, which is crucially determining all ligand–receptor binding. This disadvantage is now overcome by COSMOsim3D, which is a logical and physically sound extension of the COSMOsim method, which uses local σ-profiles on a spatial grid. This new method is used to measure intermolecular similarities on the basis of the 3D representation of the surface polarization charge densities σ of the target and the probe molecule. The probe molecule is translated and rotated in space in order to maximize the sum of local σ-profile similarities between target and probe. This sum, the COSMOsim3D similarity, is a powerful descriptor of ligand similarity and allows for a good discrimination between bioisosters and random pairs. Validation experiments using about 600 pharmacological activity classes in the MDDR database are given. Furthermore, COSMOsim3D represents a unique and very robust method for a field-based ligand–ligand alignment.