of this project is based on a recently completed project [10],
focusing on inhibiting the GPCR signaling pathway induced by a
male sea lamprey mating pheromone, 3-keto petromyzonol sulfate
(3kPZS). The successful approach described in this chapter is
equally applicable to human drug discovery for GPCRs and other
targets.
The dataset analyzed here consists of the chemical structures
and assay data for another male sea lamprey mating pheromone, the
sulfate-conjugated bile acid, 3,12-diketo-4,6-petromyzonene-24-
sulfate (DKPES, Fig.2). The 56 molecules prioritized by ligand-
based screening according to their degree of 3D DKPES similarity
were assayed for their ability to block the in vivo sea lamprey
olfactory response to DKPES, as measured by an electro-
olfactogram assay (EOG). The activity data was then analyzed
using machine learning algorithms to uncover structure–function
patterns. A brief summary of the virtual screening approach that we
used to identify inhibitory mimics of DKPES is provided in Fig.3.
As a result, 56 candidate molecules were prioritized for
biological assays based on the following criteria:
l Steroidal substructure containing molecules with a high degree
of shape and charge match to the reference pheromone, DKPES
(Fig.2).l Four DKPES analogs with oxidized (double bond-containing)
rings that are naturally produced by mature male sea lamprey
(molecule IDs: ENE 1–4, Fig.4)[22].l Diverse compounds to test the hypothesis that compounds with
the best charge and shape match will mimic DKPES (without
requiring a steroid core or sulfate tail match).l Non-steroid compounds having 3-keto or 3-hydroxy and
12-keto or 12-hydroxy matches and at least one sulfate oxygenFig. 23D structure of a favorable (low-energy) DKPES conformer, where the
functional group features corresponding to the columns in the olfactory response
dataset are highlighted with gray circles. White indicates carbon, red indicates
oxygen, and yellow indicates sulfur
Inferring Activity Discriminants 311