Docking of highly selective peptide ligands of 5HT2A/C receptors with antipsychotic activity

Abstract

Search for new ligands selective to various 5HT2 receptor subtypes is an important scientific and practical problem for experimental psychopharmacology and clinical medicine. Most of existing antagonists of the 5HT2A- and 5HT2C- subtypes have necessary anti-anxiety and antipsychotic properties, but they are partially selective to 5HT2B receptors. The activation of the latter ones leads to cardiotoxic side effects, so it significantly limits clinical use of these drugs. For the search of new highly selective ligands of 5HT2A/C receptors an in silico screening algorithm was proposed using PScore.Max and Affinity.maxPScore indices, taking into account the affinity of low molecular weight compounds to each of 5HT2 receptor subtype. Cyclic physiologically active substances of peptide nature have been proposed as new promising drugs with antipsychotic activity. Based on the CXXC library, a number of cyclopeptides with a high selectivity of the structure to the target binding sites were selected for further in vitro studies by extending the peptide chain.It was also found that a promising direction for increasing the selectivity of peptide ligands to 5HT2A/C receptors is the introduction of non-proteinogenic amino acids during the formation of a starting docking library. Their choice will be stipulated by the nature of interactions between the reference ligands and amino acid residues of the binding site.