Virtual screening with solvation and ligand-induced complementarity

Abstract

We present our database-screening tool SLIDE, which is capable of screening large data sets of organic compounds for potential ligands to a given binding site of a target protein. Its main feature is the modeling of induced complementarity by making adjustments in the protein side chains and ligand upon binding. Mean-field theory is used to balance the conformational changes in both molecules in order to generate a shape-complementary interface. Solvation is considered by prediction of water molecules likely to be conserved from the crystal structure of the ligand-free protein, and allowing them to mediate ligand interactions, if possible, or including a desolvation penalty when they are displaced by ligand atoms that do not replace the lost hydrogen bonds.A data set of over 175 000 organic molecules was screened for potential ligands to the progesterone receptor, dihydrofolate reductase, and a DNA-repair enzyme. In all cases the screening time was less than a day on a Pentium II processor, and known ligands as well as highly complementary new potential ligands were found.

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Schnecke, V., Kuhn, L.A. Virtual screening with solvation and ligand-induced complementarity. Perspectives in Drug Discovery and Design 20, 171–190 (2000). https://doi.org/10.1023/A:1008737207775

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  • bound water
  • dihydrofolate reductase
  • DNA repairenzymes
  • docking
  • drug design
  • flexibility
  • molecularrecognition
  • progesterone receptor