Molecular docking using shape descriptors

Abstract Molecular docking explores the binding modes of two interacting molecules. The technique is increasingly popular for studying protein‐ligand interactions and for drug design. A fundamental problem problem with molecular docking is that orientation space is very large and grows combinatorially with the number of degrees of freedom of the interacting molecules. Here, we describe and evaluate algorithms that improve the efficiency and accuracy of a shape‐based docking method. We use molecular organization and sampling techniques to remove the exponential time dependence on molecular size in docking calculations. The new techniques allow us to study systems that were prohibitively large for the original method. The new algorithms are tested in 10 different protein‐ligand systems, including 7 systems where the ligand is itself a protein. In all cases, the new algorithms successfully reproduce the experimentally determined configurations of the ligand in the protein.