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

Conor D Parks; Zied Gaieb; Michael Chiu; Huanwang Yang; Chenghua Shao; W Patrick Walters; Johanna M Jansen; Georgia McGaughey; Richard A Lewis; Scott D Bembenek; Michael K Ameriks; Tara Mirzadegan; Stephen K Burley; Rommie E Amaro; Michael K Gilson

doi:10.1007/s10822-020-00289-y

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

J Comput Aided Mol Des. 2020 Feb;34(2):99-119. doi: 10.1007/s10822-020-00289-y. Epub 2020 Jan 23.

Authors

Conor D Parks¹, Zied Gaieb¹, Michael Chiu¹, Huanwang Yang^{2

3}, Chenghua Shao^{2

3}, W Patrick Walters⁴, Johanna M Jansen⁵, Georgia McGaughey⁶, Richard A Lewis⁷, Scott D Bembenek⁸, Michael K Ameriks⁹, Tara Mirzadegan⁹, Stephen K Burley^{2

3}, Rommie E Amaro^{10

11}, Michael K Gilson^{12

13}

Affiliations

¹ Drug Design Data Resource, University of California, San Diego, La Jolla, CA, 92093, USA.
² RCSB Protein Data Bank, Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA.
³ San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
⁴ Relay Therapeutics, Cambridge, MA, 20139, USA.
⁵ Novartis Institutes for BioMedical Research, Emeryville, CA, 94608, USA.
⁶ Vertex Pharmaceuticals Inc, 50 Northern Ave, Boston, MA, 02210, USA.
⁷ Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002, Basel, Switzerland.
⁸ Denovicon Therapeutics, San Diego, CA, 92130, USA.
⁹ Janssen Research & Development, San Diego, CA, 92121, USA.
¹⁰ Drug Design Data Resource, University of California, San Diego, La Jolla, CA, 92093, USA. drugdesigndata@gmail.com.
¹¹ Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA, 92093-0340, USA. drugdesigndata@gmail.com.
¹² Drug Design Data Resource, University of California, San Diego, La Jolla, CA, 92093, USA. mgilson@ucsd.edu.
¹³ Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, 9500 Gilman Drive, MC0751, La Jolla, CA, 92093, USA. mgilson@ucsd.edu.

Abstract

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.

Keywords: Blinded prediction challenge; D3R; Docking; Free-energy; Ligand ranking; Scoring.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Drug Design*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Ligands
Machine Learning
Molecular Docking Simulation
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Thermodynamics

Substances

Enzyme Inhibitors
Ligands
Small Molecule Libraries
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding