3D Chemical Similarity Networks for Structure-Based Target Prediction and Scaffold Hopping.
Target identification remains a major challenge for modern drug discovery programs aimed at understanding the molecular mechanisms of drugs. Computational target prediction approaches like 2D chemical similarity searches have been widely used but are limited to structures sharing high chemical similarity. Here, we present a new computational approach called chemical similarity network analysis pull-down 3D (CSNAP3D) that combines 3D chemical similarity metrics and network algorithms for structure-based drug target profiling, ligand deorphanization, and automated identification of scaffold hopping compounds. In conjunction with 2D chemical similarity fingerprints, CSNAP3D achieved a >95% success rate in correctly predicting the drug targets of 206 known drugs. Significant improvement in target prediction was observed for HIV reverse transcriptase (HIVRT) compounds, which consist of diverse scaffold hopping compounds targeting the nucleotidyltransferase binding site. CSNAP3D was further applied to a set of antimitotic compounds identified in a cell-based chemical screen and identified novel small molecules that share a pharmacophore with Taxol and display a Taxol-like mechanism of action, which were validated experimentally using in vitro microtubule polymerization assays and cell-based assays.
Department of Chemistry and Biochemistry, ‡Program in Bioengineering, §Department of Molecular and Medical Pharmacology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, and #The Molecular Biology Institute, University of California , Los Angeles, California 90095, United States.
Yu-Chen
YC
Lo
Department of Chemistry and Biochemistry, ‡Program in Bioengineering, §Department of Molecular and Medical Pharmacology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, and #The Molecular Biology Institute, University of California , Los Angeles, California 90095, United States.
Silvia
S
Senese
Department of Chemistry and Biochemistry, ‡Program in Bioengineering, §Department of Molecular and Medical Pharmacology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, and #The Molecular Biology Institute, University of California , Los Angeles, California 90095, United States.
Robert
R
Damoiseaux
Department of Chemistry and Biochemistry, ‡Program in Bioengineering, §Department of Molecular and Medical Pharmacology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, and #The Molecular Biology Institute, University of California , Los Angeles, California 90095, United States.
Jorge Z
JZ
Torres
D000465:Algorithms; D019540:Area Under Curve; D019295:Computational Biology; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D008024:Ligands; D018716:Molecular Mimicry; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry
D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D017239:Paclitaxel