Affinity of aporphines for the human 5-HT2A receptor: insights from homology modeling and molecular docking studies.

Bioorganic & Medicinal Chemistry
Stevan PecicWayne Harding

Abstract

Analogs of nantenine were docked into a modeled structure of the human 5-HT(2A) receptor using ICM Pro, GLIDE, and GOLD docking methods. The resultant docking scores were used to correlate with observed in vitro apparent affinity (K(e)) data. The GOLD docking algorithm when used with a homology model of 5-HT(2A), based on a bovine rhodopsin template and built by the program MODELLER, gives results which are most in agreement with the in vitro results. Further analysis of the docking poses among members of a C1 alkyl series of nantenine analogs, indicate that they bind to the receptor in a similar orientation, but differently than nantenine. Besides an important interaction between the protonated nitrogen of the C1 alkyl analogs and residue Asp155, we identified Ser242, Phe234, and Gly238 as key residues responsible for the affinity of these compounds for the 5-HT(2A) receptor. Specifically, the ability of some of these analogs to establish a H-bond with Ser242 and hydrophobic interactions with Phe234 and Gly238 appears to explain their enhanced affinity as compared to nantenine.

Citations

Oct 9, 2012·Chemical Biology & Drug Design·Vani MunusamyLip Yong Chung
Mar 26, 2013·Journal of Molecular Recognition : JMR·Elizabeth Yuriev, Paul A Ramsland
Apr 29, 2014·Chemical Biology & Drug Design·Shashikanth PonnalaWayne W Harding
May 13, 2014·Journal of Chemical Information and Modeling·Krzysztof RatajAndrzej J Bojarski
Mar 19, 2013·European Journal of Organic Chemistry·Shashikanth Ponnala, Wayne W Harding
Oct 16, 2015·Biotechnology and Applied Biochemistry·Jeyachandran SivakamavalliBaskaralingam Vaseeharan
Mar 24, 2018·Prostaglandins & Other Lipid Mediators·Stevan PecicShi-Xian Deng
May 28, 2011·Journal of Medicinal Chemistry·Miles CongreveFiona H Marshall
Feb 20, 2015·Journal of Natural Products·Sudharshan Madapa, Wayne W Harding

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