LCAT MOLECULAR MODELING:APPLICATIONS TO STRUCTURE-FUNCTION RELATIONSHIPS AND TO INHIBITOR DISCOVERY

A series of large population studies have revealed the existence of a strong inverse correlation between plasma levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. Accordingly, HDL has become a major target for the development of novel therapies for the treatment of atherosclerotic cardiovascular disease. LCAT catalyzes cholesteryl ester synthesis and plays a central role in HDL structure and metabolism. Also, LCAT promotes the reverse cholesterol transport, and mediates its atheroprotective effects. Recent studies demonstrated that decreasing LCAT activity possibly has positive effects on HDL structure/function, and may represent a novel therapeutic strategy to reduce cardiovascular risk. To exploit LCAT therapeutic prospects, the availability of new potent and selective LCAT modulators is mandatory. With the present work, we identified molecules able to inhibit LCAT enzymatic activity implementing an in silico strategy. The computational approach can be deployed in two different ways: i) the availability of large chemical databases, and the computational power of the new computers allow a very efficient in silico high-throughput screening starting from the target structure and independently of any pharmacophoric hypothesis; ii) the knowledge of the active site and of the catalytic mechanism of a target can be exploited for ab initio computer-aided drug design. We have designed, through a de novo approach, an irreversible inhibitor, which is the first specific LCAT inhibitor known, and can be considered as a lead compound for the identification of new active molecules belonging to the same chemical family. In parallel, the high-throughput screening carried out on LCAT identified some very potent reversible inhibitors, which can be of interest in further drug development steps. Globally, this project produced innovative pharmacological entities to be further developed for a completely new therapeutic approach to the treatment of atherosclerotic cardiovascular diseases.