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低分子量化合物的表型筛选为重新利用的靶向药物提供了丰富的资源。

Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs.

作者信息

Lipinski Christopher A, Reaume Andrew G

机构信息

Melior Discovery, Exton, PA, United States.

出版信息

Front Pharmacol. 2022 Aug 8;13:917968. doi: 10.3389/fphar.2022.917968. eCollection 2022.

DOI:10.3389/fphar.2022.917968
PMID:36003497
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9393533/
Abstract

A target-based drug discovery strategy has led to a bias away from low molecular weight (MWT) drug discovery. Analysis of the ACS chemistry registration system shows that most low MWT drugs were first made in the time era before target-based drug discovery. Therapeutic activity among most low MWT drugs was identified in the era of phenotypic drug discovery when drugs were selected based on their phenotypic effects and before screening, mechanism of action considerations and experiences with fragment screening became known. The common perception that drugs cannot be found among low MWT compounds is incorrect based on both drug discovery history and our own experience with MLR-1023. The greater proportion of low MWT compounds that are commercially available compared to higher MWT compounds is a factor that should facilitate biology study. We posit that low MWT compounds are more suited to identification of new therapeutic activity using phenotypic screens provided that the phenotypic screening method has enough screening capacity. On-target and off-target therapeutic activities are discussed from both a chemistry and biology perspective because of a concern that either phenotypic or low MWT drug discovery might bias towards promiscuous compounds that combine on-target and off-target effects. Among ideal drug repositioning candidates (late-stage pre-clinical or clinically-experience compounds), pleiotropic activity (multiple therapeutic actions) is far more likely due to on-target effects arising where a single target mediates multiple therapeutic benefits, a desirable outcome for drug development purposes compared to the off-target alternative. Our exemplar of a low MWT compound, MLR-1023, discovered by phenotypic screening and subsequently found to have a single mechanism of action would have been overlooked based on current era medicinal chemistry precedent. The diverse therapeutic activities described for this compound by us, and others arise from the same pleiotropic lyn kinase activation molecular target. MLR-1023 serves as a proof-of-principle that potent, on target, low MWT drugs can be discovered by phenotypic screening.

摘要

基于靶点的药物发现策略导致了对低分子量(MWT)药物发现的偏见。对美国化学学会化学注册系统的分析表明,大多数低MWT药物是在基于靶点的药物发现时代之前首次合成的。大多数低MWT药物的治疗活性是在表型药物发现时代确定的,当时药物是根据其表型效应选择的,并且在筛选、作用机制考虑和片段筛选经验为人所知之前。基于药物发现历史和我们自己对MLR-1023的经验,认为在低MWT化合物中找不到药物的普遍看法是不正确的。与较高MWT化合物相比,市售低MWT化合物的比例更高,这一因素应有助于生物学研究。我们认为,只要表型筛选方法具有足够的筛选能力,低MWT化合物更适合使用表型筛选来鉴定新的治疗活性。由于担心表型或低MWT药物发现可能偏向于结合了靶标和非靶标效应的混杂化合物,因此从化学和生物学角度讨论了靶标和非靶标治疗活性。在理想的药物重新定位候选物(临床前后期或有临床经验的化合物)中,由于单个靶点介导多种治疗益处而产生的多效性活性(多种治疗作用)远比非靶标替代情况更有可能出现,这是药物开发目的的理想结果。我们的低MWT化合物范例MLR-1023是通过表型筛选发现的,随后发现具有单一作用机制,基于当前时代的药物化学先例,它可能会被忽视。我们和其他人描述的该化合物的多种治疗活性源自相同的多效性Lyn激酶激活分子靶点。MLR-1023作为一个原理证明,即可以通过表型筛选发现有效的、靶向的低MWT药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/a3ec1489adc4/fphar-13-917968-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/b0c0ea31be06/fphar-13-917968-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/d65d21e9ac3f/fphar-13-917968-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/a3ec1489adc4/fphar-13-917968-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/b0c0ea31be06/fphar-13-917968-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/d65d21e9ac3f/fphar-13-917968-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2cb/9393533/a3ec1489adc4/fphar-13-917968-g003.jpg

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