Article
Chemistry, Multidisciplinary
Elena Shanina, Sakonwan Kuhaudomlarp, Kanhaya Lal, Peter H. Seeberger, Anne Imberty, Christoph Rademacher
Summary: Carbohydrate-binding proteins, specifically lectins, are promising targets in drug discovery for combating antimicrobial resistance, yet non-carbohydrate drug-like inhibitors are still lacking. A druggable pocket in a beta-propeller lectin from Burkholderia ambifaria has been identified as a potential target for allosteric inhibitors. Future drug-discovery efforts focusing on small molecule inhibitors could benefit from targeting allosteric sites in lectins to combat antibiotic-resistant pathogens.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Pharmacology & Pharmacy
Veronica Casado-Anguera, Vicent Casado
Summary: This review summarizes both classical and non-classical allosterism, focusing on G protein-coupled receptor (GPCR) oligomers as a paradigm. The study of these new non-classical allosteric sites will expand the diversity of allosteric control and increase the therapeutic potential of allosterism.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Review
Pharmacology & Pharmacy
Mingyang Zhang, Xiaobing Lan, Xiaolong Li, Shaoyong Lu
Summary: G-protein-coupled receptors (GPCRs) are cell surface proteins that sense extracellular stimuli and mediate signaling in human physiology. Recent research has identified a conserved intracellular allosteric site in GPCRs, providing a novel avenue for biological intervention.
DRUG DISCOVERY TODAY
(2023)
Review
Chemistry, Multidisciplinary
Alexios Chatzigoulas, Zoe Cournia
Summary: Recent advances in structural biology and computational techniques have revealed allosteric mechanisms for a variety of targets, leading to the rational design of allosteric modulators as a new avenue for drug discovery. Allostery is an intrinsic property of protein conformational ensembles, allowing allosteric drug design to potentially modulate undruggable therapeutic targets, explore new chemical space, and develop mutant-specific therapies. Traditional allosteric drug discovery methods have been supplemented by more rational structure-based and ligand-based approaches, allowing for the design of bioactive allosteric ligands.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2021)
Review
Pharmacology & Pharmacy
Lauren M. Slosky, Marc G. Caron, Lawrence S. Barak
Summary: GPCRs are important cell surface receptors and drug discovery in this field faces challenges, but these may be overcome by developing biased allosteric modulators. This emerging class of GPCR ligands can modulate receptor signaling and provide opportunities for fine-tuning physiology.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Computer Science, Artificial Intelligence
Hao Tian, Xi Jiang, Peng Tao
Summary: Allostery plays a crucial role in regulating protein activity, and identifying allosteric sites is essential for drug development. The ensemble learning method presented in this study shows good performance in predicting allosteric sites, with 84.9% accuracy in the test set.
MACHINE LEARNING-SCIENCE AND TECHNOLOGY
(2021)
Review
Chemistry, Multidisciplinary
Duan Ni, Zongtao Chai, Ying Wang, Mingyu Li, Zhengtian Yu, Yaqin Liu, Shaoyong Lu, Jian Zhang
Summary: Allostery is a biological phenomenon where orthosteric sites are regulated by distal allosteric sites, triggering responses to perturbations such as ligand binding or mutations. Recent advances in biophysics, particularly in structural bioinformatics, have improved understanding of allosteric effects, leading to more rational structure-based drug discovery methods.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Duan Ni, Jiacheng Wei, Xinheng He, Ashfaq Ur Rehman, Xinyi Li, Yuran Qiu, Jun Pu, Shaoyong Lu, Jian Zhang
Summary: Allostery is a direct and efficient method for fine-tuning protein functions, gaining recognition in drug discovery. Identifying allosteric sites is a challenge for drug design, with recent studies revealing bidirectional allosteric coupling and reversed communication between orthosteric and allosteric sites. A new framework combining computational and experimental strategies has been proposed for predicting allosteric sites, demonstrating desirable performance in identifying potential cryptic sites for allosteric drug design.
Article
Biochemistry & Molecular Biology
Spencer R. Pierce, Allison L. Germann, Sophia Q. Xu, Saumith L. Menon, Marcelo O. Ortells, Hugo R. Arias, Gustav Akk
Summary: In this study, mutational analysis was used to investigate the involvement and contributions of individual intersubunit interfaces to the modulation of the alpha 1 beta 2 gamma 2L GABA(A) receptor by NS-1738 and PAM-2. The results showed that mutations to any single interface can completely abolish the potentiation by the alpha 7-PAMs. The findings are discussed in terms of energetic additivity and interactions between the different binding sites.
Review
Biochemistry & Molecular Biology
Suman Abhishek, Waghela Deeksha, Krishnapura Ranganatha Nethravathi, Mehdi D. Davari, Eerappa Rajakumara
Summary: This review discusses the characteristics and functions of modular proteins, emphasizing the importance of allostery in protein regulation and drug development.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Review
Pharmacology & Pharmacy
Duan Ni, Yaqin Liu, Ren Kong, Zhengtian Yu, Shaoyong Lu, Jian Zhang
Summary: This review comprehensively reviews bioinformatic methods for elucidating allosteric communication and discusses their successful applications in allosteric drug design. Current challenges and future perspectives are also discussed.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemistry & Molecular Biology
Farindra Kumar Mahto, Akash Bhattacharya, Swati Bhattacharya
Summary: The Hsp70 chaperone protein system is crucial for protein folding and homeostasis. Molecular dynamics simulations reveal that the Lid domain has greater conformational flexibility than previously expected.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biophysics
Hebatallah Mohamed, Ubaidullah Baryar, Amir Bashiri, Rajeevan Selvaratnam, Bryan VanSchouwen, Giuseppe Melacini
Summary: Allosteric regulation is crucial for controlling biological functions and allosteric sites are promising for selective drug targeting. However, accurately mapping allosteric sites remains challenging. This study introduces two new CHESCA-based methodologies, T-CHESCA and CLASS-CHESCA, to narrow down allosteric maps to core residues. Both methods rely on the invariance of core inter-residue correlations to changes in chemical shifts. The results provide a toolset for prioritizing and analyzing allosteric sites and have implications for disease-related mutations and the design of selective allosteric modulators.
BIOPHYSICAL JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Stefanie Kampen, David Rodriguez, Morten Jorgensen, Monika Kruszyk-Kujawa, Xinyan Huang, Michael Collins, Noel Boyle, Damien Maurel, Axel Rudling, Guillaume Lebon, Jens Carlsson
Summary: This study conducted molecular docking screens to identify allosteric modulators of the metabotropic glutamate receptor 5 (mGlu(5)). Four compounds with the highest affinities were confirmed to be negative allosteric modulators of mGlu(5) signaling.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bengi Altintel, Burcin Acar, Burak Erman, Turkan Haliloglu
Summary: Allostery, a key biological control mechanism, can be described using dynamic information flow. This study introduces a novel approach based on the Gaussian Network Model (GNM) to dissect dynamic information and reveal multi-directional allosteric pathways in protein structures. By analyzing information transfer between residues, specific residues with high dynamic capacity are identified as potential targets for structure-based rational drug design.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ping Liu, Xiaoji Cong, Shengjie Liao, Xinglong Jia, Xiaomin Wang, Wei Dai, Linhui Zhai, Lei Zhao, Jing Ji, Duan Ni, Zhiwei Liu, Yulu Chen, Lulu Pan, Wei Liu, Jian Zhang, Min Huang, Bin Liu, Minjia Tan
Summary: This study identified phosphorylation-dependent SCF substrates using a quantitative phosphoproteome approach, demonstrating the mechanism by which SCFFBXO22 recognizes a phosphodegron. FBXO22 was shown to mediate BAG3 ubiquitination and degradation, impacting tumor growth, apoptosis, and cell cycle progression.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Chemistry, Medicinal
Yiyue Feng, Yingmei Lu, Junfang Li, Honghua Zhang, Zhao Li, Hanzhong Feng, Xuemei Deng, Dan Liu, Tao Shi, Weifan Jiang, Yongxing He, Jian Zhang, Zhen Wang
Summary: By designing and synthesizing o-aminobenzamide derivatives, compounds F8 and T9 were identified as potent anti-gastric cancer agents, with F8 showing better efficacy and lower toxicity in vivo.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Ashfaq Ur Rehman, Shaoyong Lu, Abdul Aziz Khan, Beenish Khurshid, Salman Rasheed, Abdul Wadood, Jian Zhang
Summary: This review provides an overview of various theoretical approaches for predicting hidden allosteric sites in disease-related proteins, as well as in-depth examination of promising cases to uncover these hidden sites and their modulators. After years of development, MD simulations are now proving successful in providing detailed molecular insights into drug-target interactions, offering new possibilities for drug discovery and targeting previously challenging drug targets.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Review
Biochemistry & Molecular Biology
Jinyin Zha, Mingyu Li, Ren Kong, Shaoyong Lu, Jian Zhang
Summary: Allostery is an important regulatory phenomenon in life processes and disease therapy, but studying it has been challenging due to the lack of knowledge. To address this, we created the Allosteric Database (ASD) and reviewed the four categories of data in this database and how researchers have utilized them for their studies. Several new drug targets and allosteric modulators discovered through the use of ASD are also highlighted.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Duan Ni, Zongtao Chai, Ying Wang, Mingyu Li, Zhengtian Yu, Yaqin Liu, Shaoyong Lu, Jian Zhang
Summary: Allostery is a biological phenomenon where orthosteric sites are regulated by distal allosteric sites, triggering responses to perturbations such as ligand binding or mutations. Recent advances in biophysics, particularly in structural bioinformatics, have improved understanding of allosteric effects, leading to more rational structure-based drug discovery methods.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Ying Wang, Mingyu Li, Wenqi Liang, Xinchao Shi, Jigang Fan, Ren Kong, Yaqin Liu, Jian Zhang, Ting Chen, Shaoyong Lu
Summary: This study investigates the activation mechanism of a class B GPCR, human glucagon receptor-GCGR, using molecular dynamics simulations and Markov state models. The study reveals the conformational dynamics and activation process of GCGR and highlights the role of Gs in stabilizing the glucagon binding site and achieving full activation of the receptor.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Chemistry, Multidisciplinary
Cheng-xiang Wang, Ting-ting Wang, Kun-dong Zhang, Ming-yu Li, Qian-cheng Shen, Shao-yong Lu, Jian Zhang
Summary: This study investigated the antitumor potency of two pan-KRAS inhibitors, BI-2852 and BAY-293, in pancreatic ductal adenocarcinoma (PDAC). The inhibitory effects on KRAS activation were validated in vitro and their antiproliferative potency in PDAC cell lines were profiled. However, feedback regulation in the KRAS pathway weakened the inhibitor activity and variations were observed in cell proliferation inhibition in 3D organoids cultured from PDAC patient samples. These results provide a theoretical foundation for KRAS as a clinical therapeutic target and the application of pan-KRAS inhibitors in PDAC treatment, with important scientific significance in translational medicine.
ACTA PHARMACOLOGICA SINICA
(2022)
Review
Pharmacology & Pharmacy
Duan Ni, Yaqin Liu, Ren Kong, Zhengtian Yu, Shaoyong Lu, Jian Zhang
Summary: This review comprehensively reviews bioinformatic methods for elucidating allosteric communication and discusses their successful applications in allosteric drug design. Current challenges and future perspectives are also discussed.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemical Research Methods
Xiaokun Hong, Ningshan Li, Jiyang Lv, Yan Zhang, Jing Li, Jian Zhang, Hai-Feng Chen
Summary: In this study, a publicly accessible PTMint database was constructed, which contains complete experimental evidence of PTM regulation on PPIs in multiple organisms, covering various diseases. The establishment of this database helps in gaining insight into disease mechanisms, disease diagnosis, and drug discovery associated with PTM and PPI.
Article
Chemistry, Medicinal
Xiaoyue Ji, Xiaochen Cui, Zhengxin Li, Taeyoung Choi, Ying Wang, Wen Xiao, Yunshuo Zhao, Jinyin Zha, Jian Zhang, Hai-Feng Chen, Zhengtian Yu
Summary: Allosteric modulators are regulatory elements that bind to allosteric sites and can impact the properties of proteins. Molecular dynamics simulation has become an important complement to experimental methods in identifying allosteric sites. In this study, a precise force field called APSF was developed using deep learning and reweighting methods, and its performance was evaluated on multiple allosteric proteins. The results showed that APSF could effectively capture different types of allosteric pockets and sample multiple energy-minimum reference conformations. The efficiency of conformation sampling for APSF was also higher than the current force field ff14SB. These findings highlight the potential of APSF in identifying allosteric sites and screening allosteric drugs.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Jixiao He, Xinyi Liu, Chunhao Zhu, Jinyin Zha, Qian Li, Mingzhu Zhao, Jiacheng Wei, Mingyu Li, Chengwei Wu, Junyuan Wang, Yonglai Jiao, Shaobo Ning, Jiamin Zhou, Yue Hong, Yonghui Liu, Hongxi He, Mingyang Zhang, Feiying Chen, Yanxiu Li, Xinheng He, Jing Wu, Shaoyong Lu, Kun Song, Xuefeng Lu, Jian Zhang
Summary: This article introduces the role and importance of allosteric regulation in fine-tuning macromolecular function. It also highlights the recent updates in the Allosteric Database (ASD), including potential allosteric sites, allosteric protein-protein interaction modulators, and allosteric hit-to-lead compounds. These novel features make ASD a comprehensive database, facilitating allosteric target identification, mechanistic exploration, and drug discovery.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Organic
Fengkai Sun, Man Miao, Wenxue Li, Xiao-Bing Lan, Jian-Qiang Yu, Jian Zhang, Zhenyu An
Summary: An array of pyrrolo[1,2-a]quinoxaline derivatives were synthesized with moderate to good yields via the electrochemical redox reaction, involving the functionalization of C(sp(3))-H bonds and construction of C-C and C-N bonds. This atom economical reaction utilized THF as both a reactant and a solvent, with H-2 as the sole by-product.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Review
Chemistry, Multidisciplinary
Jinyin Zha, Jixiao He, Chengwei Wu, Mingyang Zhang, Xinyi Liu, Jian Zhang
Summary: Traditionally, drugs have targeted only one site on the protein surface, which limits their potency and selectivity. Dualsteric modulators, with their bivalent nature, offer a solution by targeting both orthosteric and allosteric sites, allowing for a balance of potency and selectivity, and overcoming drug resistance. They can also be used for designing fluorescent tracers and studying protein conformations.
CHEMICAL SOCIETY REVIEWS
(2023)
Meeting Abstract
Biophysics
Jun Chen, Xiaoyue Ji, Wen Xiao, Zhiyi Wu, Cheng Jiang, Jian Zhang, Zhengtian Yu, Hai-Feng Chen
BIOPHYSICAL JOURNAL
(2022)
Article
Pharmacology & Pharmacy
Qiufen Zhang, Yingyi Chen, Duan Ni, Zhimin Huang, Jiacheng Wei, Li Feng, Jun-Cheng Su, Yingqing Wei, Shaobo Ning, Xiuyan Yang, Mingzhu Zhao, Yuran Qiu, Kun Song, Zhengtian Yu, Jianrong Xu, Xinyi Li, Houwen Lin, Shaoyong Lu, Jian Zhang
Summary: This study identified a cryptic allosteric site, named Pocket Z, that is induced by the bi-directional allosteric signal triggered by NAD+ binding. Based on Pocket Z, researchers discovered a potent and selective allosteric inhibitor of SIRT6 called JYQ-42. JYQ-42 effectively inhibits SIRT6 deacetylation and demonstrates potential in suppressing cancer cell migration and pro-inflammatory cytokine production.
ACTA PHARMACEUTICA SINICA B
(2022)