Small-Scale Panel Comprising Diverse Gene Family Targets To Evaluate Compound Promiscuity

Abstract

Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects. Therefore, avoiding such compounds during early research stages would contribute to identifying compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT 2B , adenosine A 3 , M1, and GABA A ) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. Analysis of data from the PP revealed that both lipophilicity and basicity are likely to increase promiscuity, while the molecular weight does not significantly contribute. Additionally, the promiscuity assessed using our PP correlated with the occurrence of both in vitro cytotoxicity and in vivo toxicity, suggesting that the PP is useful to identify compounds with fewer toxicity concerns. In summary, this small-scale and cost-effective PP can contribute to the identification of safer compounds that would lead to a reduction in drug attrition due to safety issues.

Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective

“…Our studies also suggest that basic molecules tend to have higher toxicity odds than acidic and neutral molecules, with the exception for the low lipophilic space where acidic compounds have the highest, albeit low, toxicity odds. This result is consistent with several publications that have also demonstrated a link between the promiscuity of basic molecules in in vitro screening panels and their in vivo toxicity profile. − Regarding the neutral state, only highly lipophilic molecules have slightly higher risk than others.…”

Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors

“…Data in Table 5 illustrate the remarkable selectivity of 1- S against a large 303 human kinase panel 32 obtained with 1 μM. A small-scale promiscuity panel 33 highlighted only adenosine A3, an important receptor extensively studied as a therapeutic target in cardiovascular disorder, 34 as a possible concern. This off-target activity is not surprising for an ATP-competitive inhibitor and would require further investigation through functional assays in the event this activity is not removed during the optimization process for this chemical series.…”

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

“…Of note, the screening collection contained no drugs specifically approved as PPARγ agonists (two for PPARα: bezafibrate and gemfibrozil). These results therefore align with high promiscuity of PPARγ (comprising the largest binding pocket of the PPARs [ 14 ]) regarding the types of accepted ligands for which it has been included in safety and promiscuity panels [ 15 , 16 ].…”