Protein-Protein Interface Analysis and Hot Spots Identification for Chemical Ligand Design
Jing Chen, Xiaomin Ma, Yaxia Yuan, Jianfeng Pei and Luhua Lai
Affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Rational design for chemical compounds targeting protein-protein interactions has grown from a dream to reality after a decade
of efforts. There are an increasing number of successful examples, though major challenges remain in the field. In this paper, we will
first give a brief review of the available methods that can be used to analyze protein-protein interface and predict hot spots for chemical
ligand design. New developments of binding sites detection, ligandability and hot spots prediction from the author’s group will also be
described. Pocket V.3 is an improved program for identifying hot spots in protein-protein interface using only an apo protein structure. It
has been developed based on Pocket V.2 that can derive receptor-based pharmacophore model for ligand binding cavity. Given similarities
and differences between the essence of pharmacophore and hot spots for guiding design of chemical compounds, not only energetic
but also spatial properties of protein-protein interface are used in Pocket V.3 for dealing with protein-protein interface. In order to illustrate
the capability of Pocket V.3, two datasets have been used. One is taken from ASEdb and BID having experimental alanine scanning
results for testing hot spots prediction. The other is taken from the 2P2I database containing complex structures of protein-ligand binding
at the original protein-protein interface for testing hot spots application in ligand design.
Keywords: Protein-protein interface analysis, small molecular binder, binding site detection, ligandability, hot spots, Pocket V.3.
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