3D-QSAR studija i razvoj farmakofore za dizajn novih antidepresiva sa dejstvom na transportere serotonina i histaminske H3 receptore

Abstract

Depresija je najčešći mentalni poremećaj koji pogađa oko 350 miliona ljudi širom sveta. Selektivni inhibitori preuzimanja serotonina (SSRIs- Selective Serotonine Reuptake Inhibitors) su lekovi izbora u lečenju depresije. Rezidualni simptomi (umor, kognitivna disfunkcija, poremećaji spavanja itd.) predstavljaju značajan problem u terapiji ovog poremećaja. Antagonisti H3 receptora poboljšavaju kognitivnu funkciju i povećavaju budnost, bez nespecifičnog stimulatornog efekta, što otvara mogućnost njihovog kombinovanja sa SSRIs u cilju prevazilaženja problema rezidualnih simptoma. Do danas su sintetisana mnoga jedinjenja sa dvostrukom aktivnošću inhibitora preuzimanja serotonina/antagonista H3 receptora. Cilj rada je bio formiranje 3D-QSAR modela i strukture farmakofore jedinjenja sa dualnom aktivnošću inhibitora preuzimanja serotonina i antagonista histaminskih H3 receptora i dizajn novih antidepresiva koji ostvaruju efekat na oba ciljna mesta. Iz literature su preuzeti podaci o strukturi i aktivnosti dualnih inhibitora preuzimanja serotonina/ antagonista H3 receptora. Za pripremu molekula su korišćeni Marvin Sketch program, komponente ChemOffice paketa i Gaussian 98W. 3D-QSAR (3D Quantitative Structure-Activity Relationship) studija je sprovedena pomoću programa Pentacle 1.0.6. Formiran je 3D-QSAR model SERT (Serotonin Reuptake Transporter) inhibitora i 3D-QSAR model antagonista H3R i konstruisane su 3D-strukture farmakofora za oba ciljna mesta. Definisane su strukturne karakteristike ispitivanih jedinjenja sa najvećim uticajem na aktivnost na SERT i H3R. Oba 3D-QSAR modela su ukazala na odgovarajućeg donora vodonične veze i supstituisanu fenil grupu sa optimalnim sternim i hidrofobnim osobinama kao značajne grupe za aktivnost na oba ciljna mesta. Stoga, uvođenjem odgovarajućeg supstituenta u fenil grupu, dizajnirani su novi ligandi. Dizajnirani ligandi sa predviđenom pKi(SERT)>8,42 i sa predviđenom pKi(H3R)>8,39 odabranu su za dalju studiju. Formirane 3D-strukture farmakofora su upotrebljene za dizajn novih dualnih SERT/H3R inhibitora. Prednost dizajniranih jedinjenja u odnosu na polazna ogleda se u većoj aktivnosti na H3R uz zadržavanje optimalne aktivnosti inhibitora preuzimanja serotonina.

Depression is the most prevalent psychiatric disease, affecting 350 million people worldwide. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs. Residual symptoms (fatigue, cognitive dysfunction, sleep disturbance etc.) are important problem in therapy of depression. Since H3 receptor (H3R) antagonists improve cognition and increase wakefulness without showing nonspecific stimulant effects, development of novel dual acting antidepressants affecting serotonin transporters and histamine H3 receptors is potential solution to residual symptoms problem. To the present, many compounds with dual activity have been synthesized. The aim of this study was to create 3D-QSAR models and pharmacophore structure of dual serotonin transporter/histamine H3 ligands and to design novel ligands as potential antidepressants. Information about structure and activity of dual serotonin transporter/histamine H3 ligands was taken from references. Molecules were prepared in Marvin Sketch, ChemOffice and Gaussian 98W programs. 3D-QSAR (3D Quantitative Structure-Activity Relationship) analysis was performed by Pentacle 1.0.6 program. Two 3D-QSAR models have been built, SERT (Serotonin Reuptake Transporter) model and H3R model, and 3D-pharmacophore structures have been constructed. Structural features important for activity on both target sites have been defined. The 3D-QSAR models revealed specific hydrogen bound donor and substituted phenyl group with optimal steric and hydrophobic features as the structures significant for activity on both target sites. Therefore, by introducing the appropriate substituent into phenyl group, novel ligands have been designed. Designed ligands with predicted pKi(SERT)>8,42, and predicted pKi(H3R)>8,39 were selected for further evaluation. Formed 3D-pharmacophore structures have been used for design of novel dual serotonin transporter/histamine H3 ligands. Advantage of designed ligands compared with the lead, is that designed ligands have higher activity on histamine H3 receptor, while they maintain optimal activity on SERT.