Evolution of assay interference concepts in drug discovery

Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays

“…Since the publications regarding PAINS, by Baell and Holloway [97], and colloidal aggregators, by McGovern et al, which revealed that some substructures are often frequent hitters or promiscuous inhibitors [98], based on high-throughput screening assays, increased awareness of these categories of compounds have become important during drug discovery. However, several publications have argued that not all frequent hitters should be randomly discarded without first validating whether they are target-specific or truly promiscuous [58,[99][100][101][102]. In a recent editorial, Bajorath mentioned that the chemical integrity and specific biological activity of compounds containing PAINS substructures should be considered in the context of the whole compound and how they are embedded in the structure.…”

“…In a recent editorial, Bajorath mentioned that the chemical integrity and specific biological activity of compounds containing PAINS substructures should be considered in the context of the whole compound and how they are embedded in the structure. He also argued that "PAINS-induced activity artifacts cannot be generalized but require careful assessment on a case-by-case basis" [99]. Based on the legitimate concerns regarding PAINS and colloidal aggregates, nine American Chemical Society (ACS) editors have outlined the necessary steps that must be performed to exclude artifactual assay activities [88].…”

Discovery of highly potent pancoronavirus fusion inhibitors that also effectively inhibit COVID-19 variants from the UK (Alpha), South Africa (Beta), and India (Delta)

“…McGovern et al as frequent hitters or promiscuous inhibitors 68 in high throughput screening (HTS) campaign, the awareness of these categories of compounds became part of the equation in drug discovery. However, several publications made counter-arguments that all frequent hitters should not be randomly discarded without validating whether they are target-specific or true promiscuous 43,[69][70][71][72] . In a recent Editorial, Bajorath mentioned that the chemical integrity and specific biological activity of compounds containing PAINS substructure should be considered in the context of the whole compounds and how they are embedded in the structure.…”

“…In a recent Editorial, Bajorath mentioned that the chemical integrity and specific biological activity of compounds containing PAINS substructure should be considered in the context of the whole compounds and how they are embedded in the structure. He also argued that "PAINS-induced activity artifacts cannot be generalized but require careful assessment on a case-by-case basis" 69 . Based on the legitimate concerns on PAINS and colloidal aggregates, nine American Chemical Society (ACS) editors outlined necessary steps to rule out any artifactual assay activity 73 .…”

“…We respect both views. Thus, in the spirit of the suggestions made by the ACS Editors 73 and others 69,74 , we decided to validate the antiviral activity of the set of rhodanines that we presented here.…”