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Issue 33, 2015
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Rational design of 5-HT6R ligands using a bioisosteric strategy: synthesis, biological evaluation and molecular modelling

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Abstract

A bioisosteric strategy was successfully implemented with a screening protocol for new, potent 5-HT6R ligands. Initially, 2-[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]-1,2,3,4-tetrahydroisoquinoline (9) was found in commercial databases using a bioisosteric query (screening 5-HT6R Ki = 128 nM). Then, the hit compound was bioisosterically modified (ring alteration) leading to a novel, high affinity (Ki = 6 nM) 5-HT6R ligand (10). Extensive docking studies followed by structural interaction fingerprint analysis supported by single-crystal X-ray structures of the investigated ligands suggest different binding modes with 5-HT6R models for compounds with varying activity. An alternative anchoring point for protonated amine (D7.36) that has not been previously reported was identified.

Graphical abstract: Rational design of 5-HT6R ligands using a bioisosteric strategy: synthesis, biological evaluation and molecular modelling

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The article was received on 02 Jan 2015, accepted on 04 Mar 2015 and first published on 04 Mar 2015


Article type: Paper
DOI: 10.1039/C5RA00054H
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Citation: RSC Adv., 2015,5, 25806-25815
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    Rational design of 5-HT6R ligands using a bioisosteric strategy: synthesis, biological evaluation and molecular modelling

    J. Staroń, D. Warszycki, J. Kalinowska-Tłuścik, G. Satała and A. J. Bojarski, RSC Adv., 2015, 5, 25806
    DOI: 10.1039/C5RA00054H

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