Pub Date : 2021-09-23DOI: 10.5772/intechopen.99228
F. E. Mosa, A. El-Kadi, K. Barakat
Aryl hydrocarbon receptor (AhR) is a biological sensor that integrates environmental, metabolic, and endogenous signals to control complex cellular responses in physiological and pathophysiological functions. The full-length AhR encompasses various domains, including a bHLH, a PAS A, a PAS B, and transactivation domains. With the exception of the PAS B and transactivation domains, the available 3D structures of AhR revealed structural details of its subdomains interactions as well as its interaction with other protein partners. Towards screening for novel AhR modulators homology modeling was employed to develop AhR-PAS B domain models. These models were validated using molecular dynamics simulations and binding site identification methods. Furthermore, docking of well-known AhR ligands assisted in confirming these binding pockets and discovering critical residues to host these ligands. In this context, virtual screening utilizing both ligand-based and structure-based methods screened large databases of small molecules to identify novel AhR agonists or antagonists and suggest hits from these screens for validation in an experimental biological test. Recently, machine-learning algorithms are being explored as a tool to enhance the screening process of AhR modulators and to minimize the errors associated with structure-based methods. This chapter reviews all in silico screening that were focused on identifying AhR modulators and discusses future perspectives towards this goal.
芳烃受体(Aryl hydrocarbon receptor, AhR)是一种整合环境、代谢和内源性信号的生物传感器，在生理和病理生理功能中控制复杂的细胞反应。全长AhR包含各种结构域，包括bHLH、PAS a、PAS B和交互激活结构域。除了PAS B和转激活结构域，AhR的三维结构揭示了其子结构域相互作用的结构细节以及与其他蛋白质伙伴的相互作用。为了筛选新的AhR调制剂，采用同源建模方法建立了AhR- pas B结构域模型。利用分子动力学模拟和结合位点鉴定方法对这些模型进行了验证。此外，已知AhR配体的对接有助于确认这些结合口袋并发现承载这些配体的关键残基。在这种情况下，虚拟筛选利用基于配体和基于结构的方法筛选小分子的大型数据库，以确定新的AhR激动剂或拮抗剂，并建议从这些筛选中获得的命中值在实验生物学测试中进行验证。最近，人们正在探索机器学习算法作为一种工具，以增强AhR调制器的筛选过程，并最大限度地减少与基于结构的方法相关的误差。本章回顾了所有专注于识别AhR调制器的硅筛选，并讨论了实现这一目标的未来前景。
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Pub Date : 2021-08-24DOI: 10.5772/intechopen.98733
F. Bokhari, A. Albukhari
The process of drug discovery is challenging and a costly affair. It takes about 12 to 15 years and costs over $1 billion dollars to develop a new drug and introduce the finished product in the market. With the increase in diseases, virus spread, and patients, it has become essential to invent new medicines. Consequently, today researchers are becoming interested in inventing new medicines faster by adopting higher throughput screening methods. One avenue of approach to discovering drugs faster is the High-Throughput Screening (HTS) method, which has gained a lot of attention in the previous few years. Today, High-Throughput Screening (HTS) has become a standard method for discovering drugs in various pharmaceutical industries. This review focuses on the advancement of technologies in High-Throughput Screening (HTS) methods, namely fluorescence resonance energy transfer (FRET), biochemical assay, fluorescence polarization (FP), homogeneous time resolved fluorescence (HTRF), Fluorescence correlation spectroscopy (FCS), Fluorescence intensity distribution analysis (FIDA), Nuclear magnetic resonance (NMR), and research advances in three major technology areas including miniaturization, automation and robotics, and artificial intelligence, which promises to help speed up the discovery of medicines and its development process.
{"title":"Design and Implementation of High Throughput Screening Assays for Drug Discoveries","authors":"F. Bokhari, A. Albukhari","doi":"10.5772/intechopen.98733","DOIUrl":"https://doi.org/10.5772/intechopen.98733","url":null,"abstract":"The process of drug discovery is challenging and a costly affair. It takes about 12 to 15 years and costs over $1 billion dollars to develop a new drug and introduce the finished product in the market. With the increase in diseases, virus spread, and patients, it has become essential to invent new medicines. Consequently, today researchers are becoming interested in inventing new medicines faster by adopting higher throughput screening methods. One avenue of approach to discovering drugs faster is the High-Throughput Screening (HTS) method, which has gained a lot of attention in the previous few years. Today, High-Throughput Screening (HTS) has become a standard method for discovering drugs in various pharmaceutical industries. This review focuses on the advancement of technologies in High-Throughput Screening (HTS) methods, namely fluorescence resonance energy transfer (FRET), biochemical assay, fluorescence polarization (FP), homogeneous time resolved fluorescence (HTRF), Fluorescence correlation spectroscopy (FCS), Fluorescence intensity distribution analysis (FIDA), Nuclear magnetic resonance (NMR), and research advances in three major technology areas including miniaturization, automation and robotics, and artificial intelligence, which promises to help speed up the discovery of medicines and its development process.","PeriodicalId":198100,"journal":{"name":"High-Throughput Screening for Drug Discovery [Working Title]","volume":"62 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123917666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-06-25DOI: 10.5772/intechopen.97310
Shengya Cao, N. Martinez-Martin
Technological improvements in unbiased screening have accelerated drug target discovery. In particular, membrane-embedded and secreted proteins have gained attention because of their ability to orchestrate intercellular communication. Dysregulation of their extracellular protein–protein interactions (ePPIs) underlies the initiation and progression of many human diseases. Practically, ePPIs are also accessible for modulation by therapeutics since they operate outside of the plasma membrane. Therefore, it is unsurprising that while these proteins make up about 30% of human genes, they encompass the majority of drug targets approved by the FDA. Even so, most secreted and membrane proteins remain uncharacterized in terms of binding partners and cellular functions. To address this, a number of approaches have been developed to overcome challenges associated with membrane protein biology and ePPI discovery. This chapter will cover recent advances that use high-throughput methods to move towards the generation of a comprehensive network of ePPIs in humans for future targeted drug discovery.
{"title":"Unbiased Identification of Extracellular Protein–Protein Interactions for Drug Target and Biologic Drug Discovery","authors":"Shengya Cao, N. Martinez-Martin","doi":"10.5772/intechopen.97310","DOIUrl":"https://doi.org/10.5772/intechopen.97310","url":null,"abstract":"Technological improvements in unbiased screening have accelerated drug target discovery. In particular, membrane-embedded and secreted proteins have gained attention because of their ability to orchestrate intercellular communication. Dysregulation of their extracellular protein–protein interactions (ePPIs) underlies the initiation and progression of many human diseases. Practically, ePPIs are also accessible for modulation by therapeutics since they operate outside of the plasma membrane. Therefore, it is unsurprising that while these proteins make up about 30% of human genes, they encompass the majority of drug targets approved by the FDA. Even so, most secreted and membrane proteins remain uncharacterized in terms of binding partners and cellular functions. To address this, a number of approaches have been developed to overcome challenges associated with membrane protein biology and ePPI discovery. This chapter will cover recent advances that use high-throughput methods to move towards the generation of a comprehensive network of ePPIs in humans for future targeted drug discovery.","PeriodicalId":198100,"journal":{"name":"High-Throughput Screening for Drug Discovery [Working Title]","volume":"439 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134063680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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