D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

• Published in: Journal of computer-aided molecular design Vol. 34; no. 2; pp. 99 - 119
• Main Authors: Parks, Conor D., Gaieb, Zied, Chiu, Michael, Yang, Huanwang, Shao, Chenghua, Walters, W. Patrick, Jansen, Johanna M., McGaughey, Georgia, Lewis, Richard A., Bembenek, Scott D., Ameriks, Michael K., Mirzadegan, Tara, Burley, Stephen K., Amaro, Rommie E., Gilson, Michael K.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2020; Springer Nature B.V; Springer
• Subjects: Affinity; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animal Anatomy; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BASIC BIOLOGICAL SCIENCES; Best practice; Biochemistry & molecular biology; Biophysics; Blinded prediction challenge; CAD; Chemistry; Chemistry and Materials Science; Computer aided design; Computer Applications in Chemistry; Computer science; Crystal structure; D3R; Docking; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Free-energy; Histology; Humans; Identification methods; Ligand ranking; Ligands; Machine Learning; Molecular Docking Simulation; Morphology; Physical Chemistry; Proteins; Scoring; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Thermodynamics; Ligand ranking; Docking; Scoring; D3R; Free-energy; Blinded prediction challenge
• ISSN: 0920-654X; 1573-4951; 1573-4951
• DOI: 10.1007/s10822-020-00289-y

The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges. In Stage 1, participant ability to predict the pose and affinity of BACE1 ligands were assessed. Following the completion of Stage 1, all BACE1 co-crystal structures were released, and Stage 2 tested affinity rankings with co-crystal structures. We provide an analysis of the results and discuss insights into determined best practice methods.