Structure-based predictions of activity cliffs.
In drug discovery, it is generally accepted that neighboring molecules in a given descriptor's space display similar activities. However, even in regions that provide strong predictability, structurally similar molecules can occasionally display large differences in potency. In QSAR jargon, these discontinuities in the activity landscape are known as "activity cliffs". In this study, we assessed the reliability of ligand docking and virtual ligand screening schemes in predicting activity cliffs. We performed our calculations on a diverse, independently collected database of cliff-forming cocrystals. Starting from ideal situations, which allowed us to establish our baseline, we progressively moved toward simulating more realistic scenarios. Ensemble- and template-docking achieved a significant level of accuracy, suggesting that, despite the well-known limitations of empirical scoring schemes, activity cliffs can be accurately predicted by advanced structure-based methods.
†Department of Drug Discovery and Development-Computation, IIT-Istituto Italiano di Tecnologia, 16163 Genova, Italy.
Jarmila
J
Husby
†Department of Drug Discovery and Development-Computation, IIT-Istituto Italiano di Tecnologia, 16163 Genova, Italy.
Giovanni
G
Bottegoni
‡Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, California 92161, United States.
Irina
I
Kufareva
‡Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, California 92161, United States.
Ruben
R
Abagyan
†Department of Drug Discovery and Development-Computation, IIT-Istituto Italiano di Tecnologia, 16163 Genova, Italy.|§Department of Pharmacy and Biotechnology, Università di Bologna, 40126 Bologna, Italy.
Andrea
A
Cavalli
D018360:Crystallography, X-Ray; D062313:Databases, Pharmaceutical; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship
D008024:Ligands