NSGASEAL Application: A taste of electrostatics

The NSGSEAL application was originally designed for drug design, but it can also be applied to other properties related to the molecular structure. As an example we have analyzed a set of 10 naturally occuring and chemically diverse TRPV1 agonists. The TRPV1 receptor signals high temperature, 'Hot' flavours, and is also involved in inflammatory pain perception. It consists (probably) of 6 intra-membrane helices, with the agonists possibly interacting with residues 511 and 550. No 3-D structure of the target, or any related receptor, is available. The agonists are very flexible, and their bound conformation in the receptor is unknown.

Despite the lack of 3D information of the target and the very flexible structure of the agonists our ligand based SEAL method will rapidly identify the underlying steric and electronic similarity of a the compounds and provide an intuitive insight into their binding modes.

overlay of peppery structures

Natural TRPV1 (aka Vanilloid receptor 1) agonists, flexibly aligned on the lowest energy conformer of the hottest compound: dihydrocapsaicin. Red denotes negative electrostatic potential, blue positive potentials both computed at the solvent accessible surface of best overlapping low energy conformers.


Dataset of 10 natural TRPV1 agonists

Compound 'Hotness' Source
(as log Scoville Units)
Dihydrocapsaicin   7.2 Capsicum
Capsaicin   7.2 Capsicum
NorhydroCapsaicin   7.0 Capsicum
HomodihydroCapsaicin   6.9 Capsicum
HomoCapsaicin   6.9 Capsicum
Piperine   5.3 Black Pepper
6-Shoagol   5.1 Ginger
6-Gingerol   4.9 Ginger
Allicin   4.0 Garlic
Zingerone <4.0 Ginger

Dihydrocapsaicin DihydroCapsaicin structure

PiperinePiperine structure

6-Shoagol6-Shoagol structure

AllicinAllicin structure

ZingeroneZingerone structure