Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands

Abstract

Compounds that selectively modulate multiple targets can provide clinical benefits and are an alternative to traditional highly selective agents for unique targets. High-throughput screening (HTS) for multitarget-directed ligands (MTDLs) using approved drugs, and fragment-based drug design has become a regular strategy to achieve an ideal multitarget combination. However, the unexpected presence of pan-assay interference compounds (PAINS) suspects in the development of MTDLs frequently results in nonspecific interactions or other undesirable effects leading to artefacts or false-positive data of biological assays. Publicly available filters can help to identify PAINS suspects; however, these filters cannot comprehensively conclude whether these suspects are “bad” or innocent. Additionally, these in silico approaches may inappropriately label a ligand as PAINS. More than 80% of the initial hits can be identified as PAINS by the filters if appropriate biochemical tests are not used resulting in false positive data that are unacceptable for medicinal chemists in manuscript peer review and future studies. Therefore, extensive offline experiments should be used after online filtering to discriminate “bad” PAINS and avoid incorrect evaluation of good scaffolds. We suggest that the use of “Fair Trial Strategy” to identify interesting molecules in PAINS suspects to provide certain structure‒function insight in MTDL development.

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.…”

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.…”

rel-2-[4-Chloro-2-[(5R,6R,7S)-6-[5-(4-methoxyphenyl)-3-(2-naphthyl)-3,4-dihydropyrazole-2-carbonyl]-5-methyl-2-oxo-3,5,6,7-tetrahydrothiopyrano[2,3-d]thiazol-7-yl]phenoxy]acetic Acid

“…Thiopyrano [2,3-d]thiazole derivatives are attractive objects in modern medicinal chemistry and possess a wide range of valuable biological activities, such as anticancer [1], antimicrobial [2], antiviral [3], and antifungal [4]. A retrosynthetic approach to thiopyrano [2,3d]thiazoles leads to 5-ene-4-thiazolidinones, which contain enone fragments in their structures and in this regard are characterized as PAINs with low selectivity and high reactivity toward the nucleophilic centers of biological molecules [5,6] (Figure 1). Application of the hetero-Diels-Alder reaction is a useful synthetic tool for the transformation of the 5-ene-4-thiazolidinones to the respective thiopyrano [2,3-d]thiazoles, which enables retaining or improving the pharmacological properties and removing the PAIN features from the molecules.…”

“…H NMR (500 MHz, DMSO-d 6 , δ): 1.92 (t, J = 6.0 Hz, 3H, CH 3 ), 3.27 (dd, J = 17.8, 3.9 Hz, 1H, CH 2 ), 3.71 (s, 3H, OCH 3 ), 3.93 (dd, J = 17.8, 11.8 Hz, 1H, CH 2 ), 5.61 (dd, J = 11.8, 3.9 Hz, 1H, CH 2 ), 6,79 (sext, J = 6.9 Hz, 1H, =CH),6.88 (d, J = 8.5 Hz, 2H, arom. ), 7.06 (d, J = 15.4 Hz, 1H, =CH), 7.13 (d, J = 8.5 Hz, 2H, arom.…”