Abstract
Finding novel lead molecules is one of the primary goals in early phases of drug discovery projects. However, structurally dissimilar compounds may exhibit similar biological activity, and finding new and structurally diverse lead compounds is difficult for computer algorithms. Molecular energy fields are appropriate for finding structurally novel molecules, but they are demanding to calculate and this limits their usefulness in virtual screening of large chemical databases. In our approach, energy fields are computed only once per superposition and a simple interpolation scheme is devised to allow coarse energy field lattices having fewer grid points to be used without any significant loss of accuracy. The resulting processing speed of about 0.25 s per conformation on a 2.4 GHz Intel Pentium processor allows the method to be used for virtual screening on commonly available desktop machines. Moreover, the results indicate that grid-based superposition methods could be efficiently used for the virtual screening of compound libraries.
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Acknowledgments
The authors gratefully acknowledge the National Technology Agency of Finland (TEKES) and Finncovery Ltd. for their financial support. Orion Pharma Ltd., Juvantia Pharma, Visipoint Ltd. and CSC-Scientific Computing Ltd. are acknowledged for their help in the software development. The authors also thank Petri Kokkonen, Outi Salo and Juha Haataja for their comments and healthy criticism.
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Rönkkö, T., Tervo, A.J., Parkkinen, J. et al. BRUTUS: Optimization of a grid-based similarity function for rigid-body molecular superposition. II. Description and characterization. J Comput Aided Mol Des 20, 227–236 (2006). https://doi.org/10.1007/s10822-006-9052-4
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DOI: https://doi.org/10.1007/s10822-006-9052-4