ORIGINAL PAPER Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists Roberta Galeazzi & Luca Massaccesi & Francesco Piva & Giovanni Principato & Emilioano Laudadio Received: 10 August 2013 /Accepted: 15 December 2013 # Springer-Verlag Berlin Heidelberg 2014 Abstract Specific modulation of serotonin 5-HT 2C G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. The different efficacy of drugs targeting these receptors are due to the presence of genetic variants in population and this variability is still hard to predict. Therefore, in order to administer the more suitable drug, taking into account patient genotype, it is necessary to know the molecular effects of its gene nucleotide variations. In this work, starting from an accurate 3D model of 5-HT 2C , we focus on the prediction of the possible effect of some single nucleotide polymorphisms (SNPs) producing amino acidic changes in proximity of the 5-HT 2C ligand binding site. Particularly we chose a set of 5-HT 2C inverse agonists and antagonists which have high inhibitory activity. After predic- tion of the structures of the receptor-ligand complexes using molecular docking tools, we performed full atom molecular dynamics simulations in explicit lipid bilayer monitoring the interactions between ligands and trans-membrane helices of the receptor, trying to infer relations with their biological activity. Serotonin, as the natural ligand was chosen as refer- ence compound to advance a hypothesis able to explain the receptor inhibition mechanism. Indeed we observed a differ- ent behavior between the antagonists and inverse agonist with respect to serotonin or unbounded receptor, which could be responsible, even if not directly, of receptor’ s inactivation. Furthermore, we analyzed five aminoacidic variants of 5HT 2C receptor observing alterations in the interactions between ligands and receptor which give rise to changes of free energy values for every complex considered. Keywords 5-HT 2C . Membrane bilayer . Molecular docking . Molecular dynamics . Serotonin Introduction 5HT 2C receptor has an important role in regulating anxiety, behavioral and neuroendocrine responses to stress, pain, lo- comotor responses, food intake, and obesity [1, 2] and it is the target of drugs used to treat a variety of physiological and psychiatric conditions. This GPCR serotonin receptor is con- stitutively activated and thus, inverse agonists, such as some atypical antipsychotic drugs, attenuate receptor constitutive activity stabilizing the receptor in its inactive conformation. This enhances dopamine efflux in the nucleus accumbens and striatum. On the contrary, direct antagonists of 5-HT 2C recep- tors involved in receptor blockade are clinically used for treating depressive and anxious states. This notion is support- ed by findings that 5-HT 2C receptor antagonists stimulate dopaminergic and adrenergic pathways, exert antidepressant and anxiolytic actions in behavioral paradigms, and favor sleep and sexual function [3, 4]. On the contrary, activation of 5-HT 2C receptor is proposed for the treatment of neuropsy- chiatric disorders and obesity [5–11]. Unfortunately, antipsy- chotic drugs have variable efficacy and side effects [12–14]. The variable efficacy and side effects are due to the difficulties to design drugs targeting specific 5-HT receptors and to the difficulties to predict the individual responses of the patients. The former is because the trans-membrane regions of 5-HT2 receptors, as well as for 5-HT1, have highly homologous amino acid sequences. The latter is because single nucleotide polymorphisms (SNPs) could alter the amount of available receptor and the interaction between receptor and ligand R. Galeazzi (*) : L. Massaccesi : E. Laudadio Dipartimento di Scienze della Vita e dell’Ambiente- Università Politecnica delle Marche, via Brecce Bianche, 60128 Ancona, Italy e-mail: r.galeazzi@univpm.it F. Piva : G. Principato Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche - Università Politecnica delle Marche, via Brecce Bianche, 60128 Ancona, Italy J Mol Model (2014) 20:2120 DOI 10.1007/s00894-014-2120-0