Title
Apo2ph4: A Versatile Workflow for the Generation of Receptor-based Pharmacophore Models for Virtual Screening
Author
Jonas Kilian
Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090Vienna, Austria
Aleksandra Garifulina
Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090Vienna, Austria
... show all
Abstract
Pharmacophore models are widely used as efficient virtual screening (VS) filters for the target-directed enrichment of large compound libraries. However, the generation of pharmacophore models that have the power to discriminate between active and inactive molecules traditionally requires structural information about ligand−target complexes or at the very least knowledge of one active ligand. The fact that the discovery of the first known active ligand of a newly investigated target represents a major hurdle at the beginning of every drug discovery project underscores the need for methods that are able to derive high-quality pharmacophore models even without the prior knowledge of any active ligand structures. In this work, we introduce a novel workflow, called apo2ph4, that enables the rapid derivation of pharmacophore models solely from the three-dimensional structure of the target receptor. The utility of this workflow is demonstrated retrospectively for the generation of a pharmacophore model for the M2 muscarinic acetylcholine receptor. Furthermore, in order to show the general applicability of apo2ph4, the workflow was employed for all 15 targets of the recently published LIT-PCBA dataset. Pharmacophore-based VS runs using the apo2ph4-derived models achieved a significant enrichment of actives for 13 targets. In the last presented example, a pharmacophore model derived from the etomidate site of the α1β2γ2 GABAA receptor was used in VS campaigns. Subsequent in vitro testing of selected hits revealed that 19 out of 20 (95%) tested compounds were able to significantly enhance GABA currents, which impressively demonstrates the applicability of apo2ph4 for real-world drug design projects.
Keywords
Library and Information SciencesComputer Science ApplicationsGeneral Chemical EngineeringGeneral Chemistry
Object type
Language
English [eng]
Persistent identifier
Appeared in
Title
Journal of Chemical Information and Modeling
Volume
63
Issue
1
ISSN
1549-9596
Issued
2022
From page
101
To page
110
Publication
American Chemical Society (ACS)
Version type
Date issued
2022
Access rights
Rights
Rights statement
© 2022 The Authors
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