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揭示植物大麻素的分子靶点:反向分子对接指纹方法的机制洞察

Uncovering the molecular targets of phytocannabinoids: mechanistic insights from inverse molecular docking fingerprint approaches.

作者信息

Ravnik Vid, Jukič Marko, Furlan Veronika, Maver Uroš, Rožanc Jan, Bren Urban

机构信息

Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia.

The Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Koper, Slovenia.

出版信息

Front Pharmacol. 2025 Jun 27;16:1611461. doi: 10.3389/fphar.2025.1611461. eCollection 2025.


DOI:10.3389/fphar.2025.1611461
PMID:40657640
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12245788/
Abstract

INTRODUCTION: Among diverse chemical profile of , over 100 phytocannabinoids have been identified. The major cannabinoids -9-THC and CBD are well-studied, with approved palliative and therapeutic applications such as appetite stimulation, antiemetic therapy, pain management and epilepsy treatment. However, -9-THC's psychotropic effects limit its broader use. Minor cannabinoids exhibit therapeutic promise for a variety of conditions, potentially offering therapeutic potential without the adverse effects of -9-THC. METHODS: We explored 14 cannabinoids with an inverse molecular docking approach, docking each cannabinoid into human protein structures from the ProBiS-Dock database. We validated our inverse molecular docking protocol using retrospective metrics (ROC AUC, BEDROC, RIE, enrichment factors, total gain). We apply the novel inverse molecular docking fingerprint method to better analyze the binding patterns of different cannabinoids and extend the methodology to include hierarchical clustering of fingerprints. RESULTS: Our analysis of the inverse molecular docking results identified high scoring targets with potential as novel protein targets for minor cannabinoids, the majority associated with cancer, while others have connections with neurological disorders and inflammation. We highlighted GTPase KRas and hematopoietic cell kinase (HCK) as very promising potential targets due to favorable docking scores with almost all investigated cannabinoids. We also find multiple matrix metalloproteinases among the top targets, suggesting possible novel therapeutic opportunities in rheumatic diseases. An analysis of inverse molecular docking fingerprints shows similar binding patterns for cannabinoids with similar structures, minor structural differences still suffice to change the affinity to specific targets. Hierarchical clustering of inverse molecular docking fingerprints revealed two main clusters in protein binding pattern similarity, the first encompassing THC-class and similar cannabinoids, as well as CBL-class cannabinoids, while the second contained CBD, CBC, and CBG-class cannabinoids. Notably, CBL-class cannabinoids exhibited binding patterns more similar to THC-class cannabinoids than their CBC-class precursors, possibly offering potential therapeutic benefits akin to THC with fewer psychotropic effects. DISCUSSION: This study highlights the therapeutic potential of minor cannabinoids and identifies their potential novel protein targets. Moreover, we demonstrate the utility of inverse molecular docking fingerprinting with clustering to identify compounds with similar binding patterns as well as identify pharmacophore-related compounds in a structurally agnostic manner, paving the way for future drug discovery and development.

摘要

引言:在大麻的多种化学特征中,已鉴定出100多种植物大麻素。主要的大麻素——Δ⁹-四氢大麻酚(Δ⁹-THC)和大麻二酚(CBD)已得到充分研究,具有如刺激食欲、止吐治疗、疼痛管理和癫痫治疗等已获批准的姑息和治疗应用。然而,Δ⁹-THC的精神活性作用限制了其更广泛的使用。次要大麻素对多种病症显示出治疗前景,可能提供治疗潜力而无Δ⁹-THC的不良反应。 方法:我们采用反向分子对接方法探索了14种大麻素,将每种大麻素对接至ProBiS-Dock数据库中的人类蛋白质结构。我们使用回顾性指标(ROC曲线下面积、BEDROC、RIE、富集因子、总增益)验证了我们的反向分子对接方案。我们应用新颖的反向分子对接指纹方法来更好地分析不同大麻素的结合模式,并将该方法扩展至包括指纹的层次聚类。 结果:我们对反向分子对接结果的分析确定了得分较高的靶点,这些靶点有可能成为次要大麻素的新型蛋白质靶点,大多数与癌症相关,而其他靶点与神经系统疾病和炎症有关。由于与几乎所有研究的大麻素都有良好的对接分数,我们强调GTP酶KRas和造血细胞激酶(HCK)是非常有前景的潜在靶点。我们还在顶级靶点中发现了多种基质金属蛋白酶,这表明在风湿性疾病中可能有新的治疗机会。对反向分子对接指纹的分析表明,结构相似的大麻素具有相似的结合模式,微小的结构差异仍足以改变对特定靶点的亲和力。反向分子对接指纹的层次聚类揭示了蛋白质结合模式相似性中的两个主要聚类,第一个聚类包括THC类和类似的大麻素,以及CBL类大麻素,而第二个聚类包含CBD、CBC和CBG类大麻素。值得注意的是,CBL类大麻素的结合模式与其CBC类前体相比,更类似于THC类大麻素,可能提供类似于THC但精神活性作用较小的潜在治疗益处。 讨论:本研究突出了次要大麻素的治疗潜力,并确定了它们潜在的新型蛋白质靶点。此外,我们展示了反向分子对接指纹聚类在识别具有相似结合模式的化合物以及以结构无关的方式识别药效团相关化合物方面的效用,为未来的药物发现和开发铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/26487dbdf042/fphar-16-1611461-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/6d6b7bd4da6b/fphar-16-1611461-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/86283f1f58fc/fphar-16-1611461-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/400003de836d/fphar-16-1611461-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/95ecf2da0e43/fphar-16-1611461-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/26487dbdf042/fphar-16-1611461-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/6d6b7bd4da6b/fphar-16-1611461-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/86283f1f58fc/fphar-16-1611461-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/400003de836d/fphar-16-1611461-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/95ecf2da0e43/fphar-16-1611461-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5055/12245788/26487dbdf042/fphar-16-1611461-g005.jpg

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本文引用的文献

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Nat Rev Drug Discov. 2025-3-18

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J Med Chem. 2025-1-23

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Pharmaceuticals (Basel). 2024-11-17

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