Pharmacophores are three-dimensional arrangements of molecular features required for biological activity that are often used in virtual screening efforts to prioritize ligands for experimental screening. G protein-coupled receptors (GPCR) are integral membrane proteins of considerable interest as targets for ligand discovery and drug development. Ligand-based pharmacophore models can be constructed to identify structural commonalities between known bioactive ligands for targets including GPCR. However, structure-based pharmacophores have gained more attention as the number of publicly available, high-resolution GPCR structures have increased (93 unique GPCR as of April 13, 2021). Herein we present a method of structure-based pharmacophore generation applicable to ligand discovery for GPCR with few known ligands. Pharmacophores have been generated using the active sites of 8 class A GPCR crystal structures via automated feature annotation of 5 randomly selected functional group fragments in an attempt to sample diverse combinations of pharmacophore features to aid in virtual screening efforts. Each of the 5000 generated pharmacophores was then used to search a database containing active and decoy/inactive compounds and scored using enrichment factor and goodness-of-hit scores to assess performance. Thus far, this method has generated pharmacophores possessing the theoretical maximum enrichment factor for each receptor studied. As a proof-of-principle for this method, pharmacophores generated within two dopamine receptor 2 (D2) crystal structures have been used to identify novel candidate ligands that are currently being assessed with two <i>in vitro </i>activity assays.

Developing a Method of Automated Pharmacophore Model Generation Using Multiple Copy Simultaneous Search

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.