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Integrated Approach Using Protein and Ligand Information to Analyze Selectivity‐ and Affinity‐Determining Features of Carbonic Anhydrase Isozymes
Author(s) -
Hillebrecht Alexander,
Supuran Claudiu T.,
Klebe Gerhard
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600083
Subject(s) - carbonic anhydrase , isozyme , selectivity , chemistry , ligand (biochemistry) , carbonic anhydrase ii , quantitative structure–activity relationship , enzyme , combinatorial chemistry , biochemistry , computational biology , stereochemistry , biology , receptor , catalysis
Abstract The application and comparison of selected protein‐ and ligand‐based approaches to elucidate factors important for affinity and selectivity towards the carbonic anhydrase isozymes I, II, and IV are described. Carbonic anhydrases are abundant in pro‐ and eukaryotes. These enzymes catalyze the reversible hydration of carbon dioxide to bicarbonate and H + ions and are thus involved in many important physiological and pathophysiological processes. Due to the fact that the human carbonic anhydrase family consists of 16 closely related isozymes, the design of selective inhibitors is a special challenge for medicinal chemists. In order to extract selectivity‐determining features, we applied purely ligand‐based 3D QSAR techniques as well as qualitative comparative molecular field analyses of the targets’ binding sites using consensus principal component analysis (CPCA). The dataset for the QSAR studies was deliberately compiled from 1748 inhibitors and comprises about 140 ligands, mainly of the sulfonamide type. Additionally, we employed the novel AFMoC approach, which intrinsically combines protein and ligand information. The simultaneous use of these different techniques gives deeper insight into selectivity and affinity‐determining features and provides quantitative models for prediction.