Decoding the Molecular Target Landscape of Chalcones: An Integrated Cheminformatics Analysis Using PubChem Patent Data, Protein Target Profiling, and Bioassay Activity Mapping.

IF 3.5 4区医学 Q2 PHARMACOLOGY & PHARMACY

Current drug targets Pub Date : 2026-10-16 DOI:10.2174/0113894501502300261013021007

Stalin Arulsamy, Kiruthiga Natarajan, Suresh Kumar Krishnan, Dinesh Babu

{"title":"Decoding the Molecular Target Landscape of Chalcones: An Integrated Cheminformatics Analysis Using PubChem Patent Data, Protein Target Profiling, and Bioassay Activity Mapping.","authors":"Stalin Arulsamy, Kiruthiga Natarajan, Suresh Kumar Krishnan, Dinesh Babu","doi":"10.2174/0113894501502300261013021007","DOIUrl":null,"url":null,"abstract":"Background: Chalcones are α,β-unsaturated ketone scaffolds with broad documented bioactivity. No prior study has simultaneously integrated structural validation, PAINS assessment, chemical-space clustering, human-target classification, bioassay hit-rate benchmarking, and patent analysis within a single computational framework.Methods: Seven hundred and twenty-two PubChem chalcone compounds were curated by SMARTS-based E-configured enone validation, ECFP4 k-means clustering, Bemis-Murcko decomposition, QED/Fsp³ profiling, and PAINS filtering. Protein target profiling (476 proteins; 145 human), bioassay benchmarking (12,981 assays; 81,667 data points; ChEMBL 34), and patent analysis (2,148 records) were integrated across PubChem exports.Results: Among 722 compounds, 686 (95.0 %) were E-configured; 50 (6.9 %) were PAINS-flagged; 195 Bemis-Murcko scaffolds (SDI = 0.270); mean QED = 0.444 ± 0.175; k = 2 clusters were statistically optimal. PAINS-flagged compounds showed significantly lower QED (0.392 vs. 0.449; p < 0.001). Among 145 human protein targets across 25 functional classes, key categories included tubulin isoforms (15), ABC transporters, MAO-A/B, and AChE. Bioassay analysis yielded 18,438 active hits (22.6 % overall); hit rates were: MAO 38.6 %, ABC transporters 32.2 %, AChE 31.8 %, and anticancer 31.5 %. China dominated patent filings (38.4 %); A61P35 (anticancer) was the leading IPC category.Discussion: Chalcones demonstrate robust polypharmacological engagement across multiple target classes. The low PAINS prevalence (6.9 %) confirms chemical tractability, while the inverse correlation between hit rate and assay dataset size underscores the need to account for reporting bias. The growing patent portfolio highlights the continued translational relevance of this scaffold.Conclusion: Chalcones represent a tractable, polypharmacological scaffold with target engagement validated across 145 human proteins. Hit-rate patterns provide reliable evidence even after accounting for reporting bias, although translational claims require independent experimental validation.","PeriodicalId":10805,"journal":{"name":"Current drug targets","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current drug targets","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0113894501502300261013021007","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Chalcones are α,β-unsaturated ketone scaffolds with broad documented bioactivity. No prior study has simultaneously integrated structural validation, PAINS assessment, chemical-space clustering, human-target classification, bioassay hit-rate benchmarking, and patent analysis within a single computational framework.

Methods: Seven hundred and twenty-two PubChem chalcone compounds were curated by SMARTS-based E-configured enone validation, ECFP4 k-means clustering, Bemis-Murcko decomposition, QED/Fsp³ profiling, and PAINS filtering. Protein target profiling (476 proteins; 145 human), bioassay benchmarking (12,981 assays; 81,667 data points; ChEMBL 34), and patent analysis (2,148 records) were integrated across PubChem exports.

Results: Among 722 compounds, 686 (95.0 %) were E-configured; 50 (6.9 %) were PAINS-flagged; 195 Bemis-Murcko scaffolds (SDI = 0.270); mean QED = 0.444 ± 0.175; k = 2 clusters were statistically optimal. PAINS-flagged compounds showed significantly lower QED (0.392 vs. 0.449; p < 0.001). Among 145 human protein targets across 25 functional classes, key categories included tubulin isoforms (15), ABC transporters, MAO-A/B, and AChE. Bioassay analysis yielded 18,438 active hits (22.6 % overall); hit rates were: MAO 38.6 %, ABC transporters 32.2 %, AChE 31.8 %, and anticancer 31.5 %. China dominated patent filings (38.4 %); A61P35 (anticancer) was the leading IPC category.

Discussion: Chalcones demonstrate robust polypharmacological engagement across multiple target classes. The low PAINS prevalence (6.9 %) confirms chemical tractability, while the inverse correlation between hit rate and assay dataset size underscores the need to account for reporting bias. The growing patent portfolio highlights the continued translational relevance of this scaffold.

Conclusion: Chalcones represent a tractable, polypharmacological scaffold with target engagement validated across 145 human proteins. Hit-rate patterns provide reliable evidence even after accounting for reporting bias, although translational claims require independent experimental validation.

查看原文本刊更多论文

解码查尔酮分子靶标景观：利用PubChem专利数据，蛋白质靶标分析和生物测定活性图谱进行综合化学信息学分析。

背景：查尔酮是一种具有广泛生物活性的α，β-不饱和酮支架。之前没有研究同时集成结构验证、苦痛评估、化学空间聚类、人类目标分类、生物测定命中率基准和专利分析在一个单一的计算框架内。方法：通过SMARTS-based e -配置烯酮验证、ECFP4 k-means聚类、Bemis-Murcko分解、QED/Fsp³分析和PAINS滤波对722个PubChem查尔酮化合物进行筛选。蛋白质目标分析（476种蛋白质，145人），生物测定基准（12,981次测定，81,667个数据点，ChEMBL 34）和专利分析（2,148条记录）整合在PubChem出口中。结果：722个化合物中，686个（95.0%）具有e构型；50例（6.9%）为pains标记；195个Bemis-Murcko支架（SDI = 0.270）；平均QED = 0.444±0.175；K = 2个簇在统计上是最优的。pains标记化合物的QED显著降低（0.392比0.449,p < 0.001）。在横跨25个功能类的145个人类蛋白靶点中，关键类别包括微管蛋白异构体（15）、ABC转运蛋白、MAO-A/B和AChE。生物测定分析产生18,438个有效命中（总体22.6%）；命中率：MAO 38.6%， ABC转运蛋白32.2%,AChE 31.8%，抗癌31.5%。中国主导了专利申请（38.4%）；A61P35（抗癌）是IPC的主要类别。讨论：查尔酮在多个靶标类别中表现出强大的多药理学作用。低发生率（6.9%）证实了化学可追溯性，而命中率和分析数据集大小之间的负相关强调了考虑报告偏差的必要性。不断增长的专利组合凸显了这种支架的持续翻译相关性。结论：查尔酮是一种易于处理的多药理学支架，具有145种人类蛋白质的靶向性。即使在考虑报告偏差后，命中率模式也提供了可靠的证据，尽管翻译声明需要独立的实验验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Current drug targets 医学-药学

CiteScore

6.20

自引率

0.00%

发文量

127

审稿时长

3-8 weeks

期刊介绍： Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Current Drug Targets publishes guest edited thematic issues written by leaders in the field covering a range of current topics of drug targets. The journal also accepts for publication mini- & full-length review articles and drug clinical trial studies. As the discovery, identification, characterization and validation of novel human drug targets for drug discovery continues to grow; this journal is essential reading for all pharmaceutical scientists involved in drug discovery and development.