New Serotonin 5-HT₆Ligands from Common Feature Pharmacophore Hypotheses

Abstract

Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimer's disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commercially available database. A three-dimensional common feature pharmacophore model was developed by using the HipHop program provided in Catalyst software and was used as a query for screening the database. A recursive partitioning (RP) model which can separate active and inactive compounds was used as a filtering system. Finally a sequential virtual screening procedure (SQSP) was conducted, wherein both the common feature pharmacophore and the RP model were used in succession to improve the results. Some of the hits were selected based on druglikeness, ADME properties, structural diversity, and synthetic accessibility for real biological evaluation. The best hit compound showed a significant IC50 value of 9.6 nM and can be used as a lead for further drug development.

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

“…22 The commonly recognized pharmacophore of the 5-HT 6 R antagonists consists of four key fragments: basic nitrogen atom (PI), hydrophobic core (H), aromatic ring(s) (Ar) and dual acceptor of hydrogen bonds (HBA). [23][24][25][26][27][28] In the pharmacophore model of the 5-HT 6 R antagonists, the sulfonyl fragment is usually considered as the strong hydrogen bond acceptor. [23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5.…”

“…[23][24][25][26][27][28] In the pharmacophore model of the 5-HT 6 R antagonists, the sulfonyl fragment is usually considered as the strong hydrogen bond acceptor. [23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5. 43 forming O-H/O and N-H/O bonds, 23,27,28 respectively.…”

Integration of virtual screening with high-throughput screening for the identification of novel Rho-kinase I inhibitors

“…For pharmacophore generation, three to five inhibitors were carefully selected from each group considering activity, selectivity, and structural rigidity (Kim et al, 2008a structures were reported in the original literature, only one representative compound (usually the most potent one) from each structural class was selected. Structural redundancy is not necessary for the generation of common-feature pharmacophore models.…”

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT6receptor antagonists

“…Since then a lot of reports have been published regarding variations in N,N-dimethyl amino alkyl side chain on and around the indole nucleus and their affinity 21,32,33 ( Figure 2). Numerous selective antagonists of 5-HT 6 receptors have been disclosed during the last decade [34][35][36][37][38][39][40][41][42] and a pharmacophore model for this type of receptor antagonists has been developed based on known structurally diverse 5-HT 6 receptor antagonists [43][44][45][46][47][48][49] . In general, the model entails the positive ionizable atom (usually a secondary or tertiary amino group), a hydrogen bond acceptor group (usually a sulfone or sulfonamide group), a hydrophobic site (HYD) and -electron donor aromatic or heterocyclic ring (AR).…”