title: Deterministic pharmacophore detection via multiple flexible alignment of drug-like molecules.
abstract: We present a novel highly efficient method for the detection of a pharmacophore from a set of drug-like ligands that interact with a target receptor. A pharmacophore is a spatial arrangement of physico-chemical features in a ligand that is essential for the interaction with a specific receptor. In the absence of a known three-dimensional (3D) receptor structure, a pharmacophore can be identified from a multiple structural alignment of ligand molecules. The key advantages of the presented algorithm are: (a) its ability to multiply align flexible ligands in a deterministic manner, (b) its ability to focus on subsets of the input ligands, which may share a large common substructure, resulting in the detection of both outlier molecules and alternative binding modes, and (c) its computational efficiency, which allows to detect pharmacophores shared by a large number of molecules on a standard PC. The algorithm was extensively tested on a dataset of almost 80 ligands acting on 12 different receptors. The results, which were achieved using a set of standard default parameters, were consistent with reference pharmacophores that were derived from the bound ligand-receptor complexes. The pharmacophores detected by the algorithm are expected to be a key component in the discovery of new leads by screening large databases of drug-like molecules. A user-friendly web interface is available at http://bioinfo3d.cs.tau.ac.il/pharma. Supplementary material can be found at http://bioinfo3d.cs.tau.ac.il/pharma/reduction/.
authors.affiliation: School of Computer Science, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Schneidman-Duhovny
authors.forename: Oranit
authors.initials: O
authors.lastname: Dror
authors.forename: Yuval
authors.initials: Y
authors.lastname: Inbar
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Haim J
authors.initials: HJ
authors.lastname: Wolfson
mesh_terms: D000465:Algorithms; D002626:Chemistry, Pharmaceutical; D020650:Combinatorial Chemistry Techniques; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011487:Protein Conformation; D011955:Receptors, Drug / Q000737:chemistry*; D012984:Software
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011955:Receptors, Drug