Multiple molecular superpositioning as an effective tool for virtual database screening

CHRISTIANLEMMENa,*, MARC ZIMMERMANN andTHOMAS aLENGAUERb,c a CombiChem lnc., 1804 Embarcadero Road, Palo Alto, CA 94303, U.S.A. b German National Research Centerfor Information Technology (GMD), Institute for Algorithms and Scientific Computing (SCAl), SchloB Birlinghoven, D-53754 Sankt Augustin, Germany c University of Bonn, Research Group Professor Lengauer (FGL), Department of Computer Science, RömerstraBe 164, D-53117 Bonn, Germany

Summary. Molecular superpositioning is an important task in rational drug design. Usually it is the key step in a comparative analysis of molecules by 3D QSAR methods. Also it is helpful for the elucidation of a pharmacophore and crucial in the attempt to derive a receptor model. Generally speaking, molecular superpositioning can be seen as the analog of molecular docking if the receptor structure is not available, and direct methods are not applicable. Virtual database screening is the computational counterpart to modem experimental techniques like high throughput screening and assaying of combinatorial libraries. Both screening techniques have the common goal to detect active molecules in a large selection of compounds. Usually hundreds of thousands of candidates are to be tested, hence, time is the limiting factor and rapid processing of utmost importance. Descriptor-based methods that usually provide a simple linear encoding of the molecules meet the demands of computational speed and have been used predominantly for the task of virtual screening, for a long time. However, more powerful superposition methods have been developed during the past few years and now begin also to be applicable to screening large databases. Especially in combination with the faster methods, molecular superpositioning as the final step of a filtering protocol provides a powerful tool for virtual database screening. The present work reports on our latest developments of molecular superpositioning techniques and assessing their applicability to virtual database screening.

Key words: database filtering, molecular superpositioning, structural alignment, virtual screening

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