Quantitative Structure-Activity Relationship (QSAR) studies of carbonic anhydrase inhibitors and activators

摘要

Known for decades, the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) are widespread all over the phylogenetic tree. In the last years, it has emerged' that in addition to their well-known role for the development of diuretics or anti-glaucoma drugs, inhibitors of these enzymes may lead to novel antiobesity and anticancer therapies. Two mitochondrial CA isoforms are involved in lipogenesis and their inhibition leads to diminished fatty acid biosynthesis. Two Tran membrane, tumour associated isozymes are highly over expressed and involved in signalling/pH regulation processes within hypoxic tumors. Specific inhibitors for both types of such isoforms have been developed and some of their are in clinical evaluations. A review on Quantitative Structure-Activity Relationships (QSARs) studies of CA inhibitors is presented. The expectations of QSAR models are initially discussed, followed by model validation, estimation of predictive power of QSAR models, modeling approaches, quality of data and statistical methods used in making QSAR analyses for this class of pharmacological agents. A variety of examples of QSAR studies related to aromatic, heterocyclic and/or aliphatic sulfonamide CA inhibitors are discussed in detail, for various CA isoforms among the 15 presently known in humans, which present interest in designing antioglaucoma, antiobesity or anticancer agents/diagnostic tools. Carbonic anhydrase activators targeting human isoforms I, II, IV, VII and XIV (present among others in the brain) may lead to novel therapies for Alzheimer's disease, memory therapy and aging, since the levels of such isozymes are much diminished in the brain of patients suffering of these diseases.