Accelerating Lead Identification by High Throughput Virtual Screening: Prospective Case Studies from the Pharmaceutical Industry

• Published in: Journal of chemical information and modeling 2019-05, Vol.59 (5), p.2046-2062
• Main Authors: Damm-Ganamet, Kelly L, Arora, Nidhi, Becart, Stephane, Edwards, James P, Lebsack, Alec D, McAllister, Heather M, Nelen, Marina I, Rao, Navin L, Westover, Lori, Wiener, John J. M, Mirzadegan, Taraneh
• Format: Article
• Language: English
• Subjects: Antigens; Case studies; Chemical compounds; Kinases; Leukocytes; Ligands; Organic chemistry; Public domain; Screening; Tyrosine
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.8b00941

At the onset of a drug discovery program, the goal is to identify novel compounds with appropriate chemical features that can be taken forward as lead series. Here, we describe three prospective case studies, Bruton Tyrosine Kinase (BTK), RAR-Related Orphan Receptor γ t (RORγt), and Human Leukocyte Antigen DR isotype (HLA-DR) to illustrate the positive impact of high throughput virtual screening (HTVS) on the successful identification of novel chemical series. Each case represents a project with a varying degree of difficulty due to the amount of structural and ligand information available internally or in the public domain to utilize in the virtual screens. We show that HTVS can be effectively employed to identify a diverse set of potent hits for each protein system even when the gold standard, high resolution structural data or ligand binding data for benchmarking, is not available.