Post Processing of Protein-Compound Docking for Fragment-Based Drug Discovery (FBDD): In-Silico Structure-Based Drug Screening and Ligand-Binding Pose Prediction

Yoshifumi      Fukunishi

doi:10.2174/156802610791111452

Abstract

For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naive protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, postprocessing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

Keywords: In-silico drug screening, protein-compound docking, virtual screening, Pharmacogram method, Consensus Ligand Binding mode Analysis method, Fragment Screening by Replica Generation, Smooth Reaction Path Generation, Filling potential