Chemical superposition and pharmacophore elucidation by SCAPFOld: Self-consistent atomic property field optimization


Maxim Totrov, Modeling and Drug Design, Molsoft, LLC, 3366 North Torrey Pines Court, S. 300, La Jolla, CA 92037
Accurate multiple ligand superposition and subsequent elucidation of the pharmacophoric features are the key steps in ligand-based drug design process. The proposed method is based on iterative optimization of a composite 7-component atomic property field. Ligand conformations and positions are optimized by montecartlo minimization procedure in internal coordinates in the property field potentials combined with the internal force field energy. Up to several hundreds of ligands can be simultneously flexibly superimposed. Rigid 'seed' structures can be included in the ligand set to drive the process towards preferred conformations deduced from experimental data such as X-ray structures. The resulting optimal self-consistent atomic property field can be used to elucidate a pharmacophoric model by locating the maxima of the field components corresponding to the classical pharmacophoric properties. The results are illustrated on Figure 1, depicting the conformations of 25 inhibitors of CDK2 flexibly superimposed by SCAPFOld procedure. Yellow, blue and red blobs are the isosurfaces contouring high potential value regions in space for, respectively, the hydrophobic, hydrogen bond donor and hydrogen bond acceptor components of the property field. Test results for several datasets will be presented and discussed.