title: Application of the 4D fingerprint method with a robust scoring function for scaffold-hopping and drug repurposing strategies.
abstract: Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza-Wei-Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 μM against MycP1 and possessed high structural diversity, which provides departure points for further structure-activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy.
authors.affiliation: Department of Molecular and Cellular Biochemistry, ‡Center for Structural Biology, §Center for Pharmaceutical Research and Innovation, College of Pharmacy, ∥Molecular Modeling and Biopharmaceutical Center, and ⊥Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Adel
authors.initials: A
authors.lastname: Hamza
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wagner
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Wei
authors.forename: Stefan
authors.initials: S
authors.lastname: Kwiatkowski
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Korotkov
mesh_terms: D000465:Algorithms; D000995:Antitubercular Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D058947:Bacterial Secretion Systems / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D062313:Databases, Pharmaceutical; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000201:enzymology; D055553:Prescription Drugs / Q000737:chemistry*; D011485:Protein Binding; D012107:Research Design; D012984:Software; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D004791:Enzyme Inhibitors; D008024:Ligands; D055553:Prescription Drugs; D013381:Subtilisins; C471626:mycosin-1, Mycobacterium tuberculosis