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. 2010 Jul;38(Web Server issue):W424-30.
doi: 10.1093/nar/gkq480. Epub 2010 Jun 2.

SiMMap: a web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties

Yen-Fu Chen  1 , Kai-Cheng Hsu, Shen-Rong Lin, Wen-Ching Wang, Yu-Chi Huang, Jinn-Moon Yang
Affiliations

SiMMap: a web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties

Yen-Fu Chen et al. Nucleic Acids Res. 2010 Jul.

Abstract

The protein-ligand interacting mechanism is essential to biological processes and drug discovery. The SiMMap server statistically derives site-moiety map with several anchors, which describe the relationship between the moiety preferences and physico-chemical properties of the binding site, from the interaction profiles between query target protein and its docked (or co-crystallized) compounds. Each anchor includes three basic elements: a binding pocket with conserved interacting residues, the moiety composition of query compounds and pocket-moiety interaction type (electrostatic, hydrogen bonding or van der Waals). We provide initial validation of the site-moiety map on three targets, thymidine kinase, and estrogen receptors of antagonists and agonists. Experimental results show that an anchor is often a hot spot and the site-moiety map can help to assemble potential leads by optimal steric, hydrogen bonding and electronic moieties. When a compound highly agrees with anchors of site-moiety map, this compound often activates or inhibits the target protein. We believe that the site-moiety map is useful for drug discovery and understanding biological mechanisms. The SiMMap web server is available at http://simfam.life.nctu.edu.tw/.

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Figures

Figure 1.
Figure 1.
Overview of the SiMMap server for the site-moiety map using herpes simplex virus type-1 thymidine kinase (TK) and 1000 docked compounds as the query. (A) Main procedure; (B) the merged protein–compound interaction profile; (C) the pocket–moiety interaction preferences of three anchors: E1 (electrostatic), H2 (hydrogen-bonding) and V1 (van der Waals). Each anchor consists of a binding pocket with conserved interacting residues, the moiety composition and anchor type; (D) the site-moiety map with four anchors.
Figure 2.
Figure 2.
The SiMMap server analysis results using estrogen receptor (ER) and 1000 docked compounds as the query. (A) The user interface for uploading target protein structure and docked compounds. (B) The site-moiety map has one hydrogen-bonding and three van der Waals anchors for ER. Each anchor contains the moiety structures and composition, anchor type, and key residues in the binding pocket. (C) The details of moiety structures and residue–moiety interactions in the H1 anchor. (D) The SiMMap scores, ranks and the relationships between anchors and moieties of query compounds.
Figure 3.
Figure 3.
The relationships between the site-moiety map and 15 co-crystallized ligands of TK. (A) The mapping between four inferred anchors (binding pocket with conserved interacting residues) and these 15 ligands in the active site. (B) The moieties of these 15 ligands in each anchor. (C) The moiety compositions of 1000 docked compounds (SiMMap) and these 15 ligands.
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