Amine promiscuity and toxicology analysis

Lee, Esther C.Y.; Steeno, Gregory S.; Wassermann, Anne Mai; Zhang, Liying; Shah, Falgun; Price, David A.

doi:10.1016/j.bmcl.2016.11.085

Cited by 9 publications

(6 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On average, when both the median and average were utilized, compounds with a high hit rate in the PP tended to have high MB-pK a values (Figure 3B), suggesting that compounds with basic functional groups are likely to show promiscuous interaction behavior. Since we confirmed a similar relationship between promiscuity and physicochemical properties as in previous reports, 16,24,25 the miniaturized PP is considered to reflect the results obtained from large-scale panels.…”

Section: ■ Results and Discussionsupporting

confidence: 88%

“…24,25 The consensus is that interaction promiscuity is positively correlated with the clogP 24,25 and pK a (for basic molecules). 16,24,25 To confirm whether this tendency is observed in our PP, we examined the relationship between the number of hit targets in the PP and the physicochemical properties of the test compounds. Initially, we investigated the influence of clopP on the number of hit targets.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Even though the GPCR family is involved in various pharmacological and toxicological effects, this family accounts for only ∼4% of the human-protein-coding genome (∼800 out of 20 000 in total) 15 and is not the only gene family related to toxicity. 9 Given that basic compounds tend to have higher interaction promiscuity, particularly toward GPCRs, 16 a small-scale panel that covers additional physicochemical property space, such as neutral and acidic compounds, should be useful to investigate the interaction promiscuity of a wide variety of gene families.…”

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Sameshima

Yukawa

Hirozane

et al. 2019

Chem. Res. Toxicol.

View full text Add to dashboard Cite

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.

show abstract

Section: ■ Results and Discussionsupporting

confidence: 88%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sameshima

Yukawa

Hirozane

et al. 2019

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…However, more recently, Lee et al have published on the role of amine promiscuity and toxicological findings as categorized by primary, secondary, and tertiary amines. This work illustrated that primary amines are less promiscuous than secondary or tertiary amines based on an analysis of 938 basic compounds tested on 100 targets …”

Section: Discussionmentioning

confidence: 99%

“…This work illustrated that primary amines are less promiscuous than secondary or tertiary amines based on an analysis of 938 basic compounds tested on 100 targets. 42 Finally, the notion of molecular complexity has been described in the literature by Leach and Hann as a model to describe molecular interactions and the probability of single or multiple binding events. 43 In this model, a less complex molecule (e.g., a fragment) has a higher probability of binding to a given target than a more complex molecule due to higher chances for mismatches with the ligand pocket.…”

Section: T H I S C O N T E N T Imentioning

confidence: 99%

Promiscuity of in Vitro Secondary Pharmacology Assays and Implications for Lead Optimization Strategies

2019

View full text Add to dashboard Cite

We conducted an analysis on screening data generated from 1445 compounds against a panel of 130 enzymes, ion channels, and receptors to assess secondary pharmacological risks. Hit rates of these targets as well as physicochemical properties for those hits were evaluated. A majority of targets yielded hits with higher clogP, molecular weight, and more basic character than inactive compounds. Although most targets favored lipophilic hits, the average clogP of hits at a given target did not correlate with its hit rate. Furthermore, a matched pair analysis was completed to determine structural changes that impacted off-target activities. A correlation of binding assays used in this analysis illustrated that some pharmacologically related binding assays are highly correlative and may be substituted for a smaller set of surrogate assays.

show abstract

Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective

Johnstone

Albert

2017

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

New strategies to potentially improve drug safety and efficacy emerge with allosteric programs. Biased allosteric modulators can be designed with high subtype selectivity and defined receptor signaling endpoints, however, selecting the most meaningful parameters for optimization can be perplexing. Historically, "potency hunting" at the expense of physicochemical and pharmacokinetic optimization has led to numerous tool compounds with excellent pharmacological properties but no path to drug development. Conversely, extensive physicochemical and pharmacokinetic screening with only post hoc bias and allosteric characterization has led to inefficacious compounds or compounds with on-target toxicities. This field is rapidly evolving with new mechanistic understanding, changes in terminology, and novel opportunities. The intent of this digest is to summarize current understanding and debates within the field. We aim to discuss, from a medicinal chemistry perspective, the parameter choices available to drive SAR.

show abstract

Amine promiscuity and toxicology analysis

Cited by 9 publications

References 18 publications

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

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

Promiscuity of in Vitro Secondary Pharmacology Assays and Implications for Lead Optimization Strategies

Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective

Contact Info

Product

Resources

About