Assessing Molecular Docking Tools to Guide Targeted Drug Discovery of CD38 Inhibitors

• Published in: International journal of molecular sciences Vol. 21; no. 15; p. 5183
• Main Authors: Boittier, Eric D, Tang, Yat Yin, Buckley, McKenna E, Schuurs, Zachariah P, Richard, Derek J, Gandhi, Neha S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.07.2020; MDPI
• Subjects: Accuracy; ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - chemistry; Affinity; Aging; Algorithms; Binding Sites; Calcium; Calcium ions; CD38 (cluster of differentiation 38 protein); CD38 antigen; Chemical fingerprinting; Computer applications; Correlation analysis; Crystal structure; Crystallization; Databases, Protein; DNA damage; drug design; Drug development; Drug Discovery - methods; enzyme inhibitor; Enzyme Inhibitors - chemistry; Gold; Learning algorithms; Ligands; Machine Learning; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - chemistry; Metabolism; Molecular docking; Molecular Docking Simulation - methods; Optimization; Physics; Physiological effects; Power plants; Predictions; Protein Conformation; Proteins; scoring functions; Software; scoring functions; CD38 (cluster of differentiation 38 protein); molecular docking; enzyme inhibitor; drug design
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21155183

A promising protein target for computational drug development, the human cluster of differentiation 38 (CD38), plays a crucial role in many physiological and pathological processes, primarily through the upstream regulation of factors that control cytoplasmic Ca concentrations. Recently, a small-molecule inhibitor of CD38 was shown to slow down pathways relating to aging and DNA damage. We examined the performance of seven docking programs for their ability to model protein-ligand interactions with CD38. A test set of twelve CD38 crystal structures, containing crystallized biologically relevant substrates, were used to assess pose prediction. The rankings for each program based on the median RMSD between the native and predicted were Vina, AD4 > PLANTS, Gold, Glide, Molegro > rDock. Forty-two compounds with known affinities were docked to assess the accuracy of the programs at affinity/ranking predictions. The rankings based on scoring power were: Vina, PLANTS > Glide, Gold > Molegro >> AutoDock 4 >> rDock. Out of the top four performing programs, Glide had the only scoring function that did not appear to show bias towards overpredicting the affinity of the ligand-based on its size. Factors that affect the reliability of pose prediction and scoring are discussed. General limitations and known biases of scoring functions are examined, aided in part by using molecular fingerprints and Random Forest classifiers. This machine learning approach may be used to systematically diagnose molecular features that are correlated with poor scoring accuracy.