In Vitro Screening for Drug Repositioning

Abstract

Drug repositioning or repurposing has received much coverage in the scientific literature in recent years and has been responsible for the generation of both new intellectual property and investigational new drug submissions. The literature indicates a significant trend toward the use of computational-or informatics-based methods for generating initial repositioning hypotheses, followed by focused assessment of biological activity in phenotypic assays. Another viable method for drug repositioning is in vitro screening of known drugs or drug-like molecules, initially in disease-relevant phenotypic assays, to identify and validate candidates for repositioning. This approach can use large compound libraries or can focus on subsets of known drugs or drug-like molecules. In this short review, we focus on ways to generate and validate repositioning candidates in disease-related in vitro and phenotypic assays, and we discuss specific examples of this approach as applied to a variety of disease areas. We propose that in vitro screens offer several advantages over biochemical or in vivo methods as a starting point for drug repositioning.

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia

“…The topic of the present study, in silico drug repositioning uses publically available data on drugs in combination with bioinformatics tools to systematically identify interactions between compounds and targets (Dubus et al 2009;Wilkinson and Pritchard 2015), in our case generated using disease genetics. This approach has the potential to efficiently identify compounds for target validation studies and reduce the time-to-market.…”

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

“…Therefore, new drugs for the treatment of drug-resistant S. aureus biofilm infections are still desperately needed. However, due to the high cost, long incubation period, and low success rate of new drug development, the private pharmaceutical sector has withdrawn from antibiotic discovery (5). In response, individual or collaborative efforts in notfor-profit organizations and academic institutions focusing on novel or nontraditional approaches for antibiotic discovery have increased.…”

“…In response, individual or collaborative efforts in notfor-profit organizations and academic institutions focusing on novel or nontraditional approaches for antibiotic discovery have increased. One such approach is to explore the potential use of existing drugs in disease areas outside their original indications, otherwise known as "drug repositioning" or "drug repurposing" (5). Finding new uses for existing drugs can be achieved either on the basis of a detailed understanding of the chemistry of individual compounds and their potential targets from in silico modeling followed by in vitro cell culture and in vivo animal studies or directly by screening a large library of compounds in diseaserelevant phenotypic assays, thus allowing an unbiased approach to obtain successful hits (5).…”

“…One such approach is to explore the potential use of existing drugs in disease areas outside their original indications, otherwise known as "drug repositioning" or "drug repurposing" (5). Finding new uses for existing drugs can be achieved either on the basis of a detailed understanding of the chemistry of individual compounds and their potential targets from in silico modeling followed by in vitro cell culture and in vivo animal studies or directly by screening a large library of compounds in diseaserelevant phenotypic assays, thus allowing an unbiased approach to obtain successful hits (5). The latter approach can accelerate and bring down the costs of the drug discovery process if an appropriate library of FDA-approved compounds with substantial diversity, drug-like properties, and acceptable safety profiles is chosen and a relevant phenotypic assay that closely mimics the in vivo conditions is used.…”

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

“…If cells are sensitized to a library compound in the presence of the test agent, compared with the vehicle control, the combination might be clinically important and worthy of follow-up (Uitdehaag et al, 2015). This strategy is particularly powerful when searching for synergies among a library of agency-registered compounds, such as the National Center for Advancing Translational Sciences Pharmaceutical Collection (Huang et al, 2011), which might accelerate long-term clinical trial approval (Wilkinson and Pritchard, 2015).…”