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)
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sandra Postel, Lisa Wissler, Carina A. Johansson, Anders Gunnarsson, Euan Gordon, Barry Collins, Marie Castaldo, Christian Koehler, David oeling, Patrik Johansson, Linda Froederberg Roth, Brice Beinsteiner, Ian Dainty, Stephen Delaney, Bruno P. Klaholz, Isabelle M. L. Billas, Karl Edman
Summary: This study reveals how the glucocorticoid receptor forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore. It provides insights into how receptor modifications drive disease progression and offers a platform for future drug design.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Arum Wu, David Salom, John D. Hong, Aleksander Tworak, Kohei Watanabe, Els Pardon, Jan Steyaert, Hideki Kandori, Kota Katayama, Philip D. Kiser, Krzysztof Palczewski
Summary: By discovering specific Nbs that bind to the extracellular surface of rhodopsin and modulate the thermodynamics of its activation process, researchers have revealed the secondary structure of Nbs and how they affect GPCR signaling states. Nbs also improve protein misfolding in disease-associated mutant rhodopsin, making them potential therapeutic agents for related diseases.
NATURE COMMUNICATIONS
(2023)
Article
Neurosciences
Bing Zhang, Xili Yang, Luyu Ye, Rui Liu, Binglu Ye, Weijia Du, Fuyi Shen, Qian Li, Fan Guo, Jinqi Liu, Fei Guo, Yang Li, Zhendong Xu, Zhiqiang Liu
Summary: Ketamine demonstrates rapid antidepressant effects at subanaesthetic doses, but the understanding of its mechanism is still limited. By increasing the excitability of the mPFC, ketamine exerts its antidepressant effects, with a critical role played by the GABAergic system in the mPFC.
Article
Multidisciplinary Sciences
Wessel A. C. Burger, Vi Pham, Ziva Vuckovic, Alexander S. Powers, Jesse I. Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian C. Felder, Radostin Danev, Ron O. Dror, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The M4 muscarinic acetylcholine receptor is a significant drug target for the treatment of psychosis, cognition, and addiction. The clinical trial of xanomeline has shown promise in improving symptoms and the cryo-EM structure reveals the binding mechanism, providing insight into its complex pharmacology.
NATURE COMMUNICATIONS
(2023)
Article
Psychiatry
Pei Shang, Ada Man-Choi Ho, Maximilian Tufvesson-Alm, Daniel R. Lindberg, Caroline W. Grant, Funda Orhan, Feride Eren, Maria Bhat, Goran Engberg, Lilly Schwieler, Helena Fatouros-Bergman, Sophie Imbeault, Ryan M. Iverson, Surendra Dasari, Fredrik Piehl, Simon Cervenka, Carl M. Sellgren, Sophie Erhardt, Doo-Sup Choi
Summary: This study utilized metabolomics analysis to identify psychosis-associated metabolites in CSF and serum samples, revealing increased levels of CSF serotonin (5-HT) and potential biomarkers for psychosis. Most metabolites remained stable at the 18-month follow-up, indicating improvement in positive symptoms and cognitive functions. Changes in CSF and serum metabolites between baseline and follow-up provided insights into psychosis pathogenesis and progression.
TRANSLATIONAL PSYCHIATRY
(2022)
Article
Neurosciences
Kevin M. Manz, Jose C. Zepeda, Zack Zurawski, Heidi E. Hamm, Brad A. Grueter
Summary: The nucleus accumbens (NAc) plays a role in behaviors such as addiction and depression. G(i/o)-coupled G-protein-coupled receptors (GPCRs) at glutamatergic synapses onto medium spiny projection neurons (MSNs) regulate these behaviors. In this study, the authors investigated which G(i/o) systems in the NAc utilize G beta gamma-SNARE signaling to inhibit glutamatergic transmission. They found that SNAP25 contributes significantly to the actions of certain GPCRs in dampening glutamatergic transmission.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Review
Chemistry, Medicinal
Danish Mahmood, Sattam K. Alenezi, Md. Jamir Anwar, Faizul Azam, Kamal A. Qureshi, Mariusz Jaremko
Summary: Psychedelics, when used in medically supervised low doses, have shown good tolerance and efficacy in treating various neuropsychiatric disorders. They primarily work by modulating serotonin receptors to impact brain connectivity and may share some common pathways with certain antipsychotic drugs through complex neurotransmitter interactions.
Article
Chemistry, Medicinal
Magda Kondej, Tomasz M. Wrobel, Katarzyna M. Targowska-Duda, Anton Leandro Martinez, Alba Paz, Olga Wronikowska-Denysiuk, Maria Loza, Marian Castro, Agnieszka A. Kaczor, Oliwia Koszta, Piotr Stepnicki, Agata Zieba
Summary: This study discovered a class of compounds with multitarget characteristics, showing strong affinity for dopamine and serotonin receptors involved in schizophrenia pharmacotherapy. The compounds displayed low affinity for off-target receptors and demonstrated favorable pharmacological properties.
Article
Behavioral Sciences
Adriana Jesus Souza, Isadora L. Cortez, Nicole R. Silva, Joao Francisco C. Pedrazzi, Luana B. Domingos, Matheus Silva Braga, Thamyris Santos-Silva, Elaine A. Del-Bel, Leonardo B. M. Resstel, Guanguan Li, Md Yeunus Mian, Dishary Sharmin, Francisco S. Guimaraes, James M. Cook, Felipe Gomes
Summary: The effects of two positive allosteric modulators of α5-GABA(A)R were evaluated in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties. Results showed distinct behavioral responses in male and female mice, suggesting the potential of these modulators for the treatment of psychiatric disorders.
BEHAVIOURAL BRAIN RESEARCH
(2022)
Review
Chemistry, Medicinal
Akash Rathore, Vivek Asati, Sushil Kumar Kashaw, Shivangi Agarwal, Deepa Parwani, Sushanta Bhattacharya, Chaitali Mallick
Summary: Schizophrenia is a chronic neuropsychiatric disorder affecting nearly 1% of the global population, and there is a need to explore novel potential lead compounds for its treatment. Research suggests that various piperidine and piperazine derivatives have shown promising activity against dopamine and serotonin receptors involved in schizophrenia.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Alberto Fernandez-Teruel
Summary: This perspective paper addresses the question of whether inhibition of GABA-A receptor-mediated synaptic transmission is involved in antidepressant-like actions and the therapeutic effects of conventional antidepressant drugs. It also discusses whether the recent development of negative allosteric modulators of the alpha5-GABA-A receptor represents significant progress in our understanding of the neurobiology and treatment of depression.
CURRENT NEUROPHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
James Neef, Daniel S. Palacios
Summary: Current pharmacological treatments for schizophrenia mainly target the D2 receptor to alleviate positive symptoms but fail to address negative and cognitive symptoms, leading to high levels of patient non-compliance. Novel mechanisms with improved tolerability are urgently needed along with medicines to treat all symptoms, including those that have reached clinical development with non-D2 mechanisms. The potential for disease modifying treatments for schizophrenia will also be discussed.
RSC MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Na-Young Song, Xin Li, Buyong Ma, Jami Willette-Brown, Feng Zhu, Chengfei Jiang, Ling Su, Jyoti Shetty, Yongmei Zhao, Gongping Shi, Sayantan Banerjee, Xiaolin Wu, Bao Tran, Ruth Nussinov, Michael Karin, Yinling Hu
Summary: The low expression of IKK alpha in lung adenocarcinoma cells is associated with increased monocyte-derived macrophages and regulatory T cells, as well as elevated levels of cytokines that recruit macrophages and induce Tregs. These cytokines stimulate the progression of lung adenocarcinoma by promoting the recruitment of macrophages and generating Tregs through TNF/TNFR2/c-Rel signaling cascade. Depletion of TNFR2, c-Rel, or TNF inhibits Treg generation and lung tumorigenesis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Multidisciplinary
Xiaoqin Pan, Xuan Lin, Dongsheng Cao, Xiangxiang Zeng, Philip S. Yu, Lifang He, Ruth Nussinov, Feixiong Cheng
Summary: This review introduces guidelines on utilizing deep learning methodologies and tools for drug repurposing, which is of great importance in drug development. The article summarizes the commonly used bioinformatics and pharmacogenomics databases for drug repurposing and discusses the recently developed sequence-based and graph-based representation approaches as well as state-of-the-art deep learning-based methods. The applications of drug repurposing in fighting the COVID-19 pandemic are presented, along with an outline of future challenges.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2022)
Article
Chemistry, Medicinal
Hao Zhang, Duan Ni, Jigang Fan, Minyu Li, Jian Zhang, Chen Hua, Ruth Nussinov, Shaoyong Lu
Summary: This study reveals the transition pathway of the C-terminal hypervariable region (HVR) of K-Ras4B, identifies key conformational substates, and uncovers important interactions between the HVR and the catalytic domain. These findings are essential for a deeper understanding of the HVR transition mechanism and the regulation of K-Ras4B activity.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Obstetrics & Gynecology
Nandor Gabor Than, Roberto Romero, Daniel Gyorffy, Mate Posta, Gaurav Bhatti, Bogdan Done, Piya Chaemsaithong, Eunjung Jung, Manaphat Suksai, Francesca Gotsch, Dahiana M. Gallo, Mariachiara Bosco, Bomi Kim, Yeon Mee Kim, Tinnakorn Chaiworapongsa, Simona W. Rossi, Andras Szilagyi, Offer Erez, Adi L. Tarca, Zoltan Papp
Summary: This study identified different molecular subclasses of preeclampsia through longitudinal proteomic profiling, laying the foundation for the development of new diagnostic and personalized tools for prevention.
JOURNAL OF PERINATAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Yonglan Liu, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Summary: Bcr-Abl, a nonreceptor tyrosine kinase, plays a crucial role in leukemias, particularly chronic myeloid leukemia (CML). The fusion of Bcr and Abl leads to constitutive activation of Bcr-Abl. Oligomerization of Bcr-Abl is critical for its membrane clustering, MAPK signaling, and cell proliferation. Understanding the structural basis of Bcr-Abl oligomerization can guide the development of novel drugs targeting this process.
Letter
Oncology
Mingzhen Zhang, Ryan Maloney, Yonglan Liu, Hyunbum Jang, Ruth Nussinov
CANCER COMMUNICATIONS
(2023)
Review
Cell Biology
Xiangxiang Zeng, Fei Wang, Yuan Luo, Seung-Gu Kang, Jian Tang, Felice C. Lightstone, Evandro F. Fang, Wendy Cornell, Ruth Nussinov, Feixiong Cheng
Summary: The recent advances of AI and deep generative models in medicinal applications, specifically in drug discovery and development, have proven their utility. This review provides an updated and accessible guide for the computational drug discovery and development community, discussing classical and newly developed AI approaches. The theoretical frameworks for representing chemical and biological structures and their applications are described, along with the challenges and future directions of multimodal deep generative models for accelerating drug discovery.
CELL REPORTS MEDICINE
(2022)
Review
Pharmacology & Pharmacy
Ruth Nussinov, Mingzhen Zhang, Yonglan Liu, Hyunbum Jang
Summary: Drug discovery is a highly challenging and significant interdisciplinary aim. The success of AlphaFold, an AI-powered technology, has raised hopes for drug discovery, but its limitations need to be considered. Improving AlphaFold's performance in active state models can enhance the success rate of rational drug design.
DRUG DISCOVERY TODAY
(2023)
Article
Biochemistry & Molecular Biology
Istvan Hajdu, Barbara M. Vegh, Andras Szilagyi, Peter Zavodszky
Summary: The amyloidogenic processing of APP depends on its phosphorylation by ROCK2 and the phosphorylation of BACE1. The binding mechanisms and structural details of the interactions between APP-ROCK2 and BACE1-ROCK2 are unknown. In this study, it was found that BACE1 weakly binds to ROCK2, inducing an allosteric conformational change, and APP strongly binds to the ROCK2-BACE1 complex. The results suggest that there are two binding sites involved in the ROCK2-APP interaction: the substrate-binding groove and the allosteric binding site.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Physical
Mingzhen Zhang, Yonglan Liu, Hyunbum Jang, Ruth Nussinov
Summary: Kinase drug selectivity is a challenge in cancer research. Researchers propose a protocol to identify unique geometric features in the drug pocket that can distinguish one kinase from others. They analyze the structural principles of kinase drug selectivity using experimental structures and artificial intelligence. The results show that there are binary units in the kinome that can distinguish kinases from each other.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Review
Biophysics
Ruth Nussinov, Bengi Ruken Yavuz, M. Kaan Arici, Habibe Cansu Demirel, Mingzhen Zhang, Yonglan Liu, Chung-Jung Tsai, Hyunbum Jang, Nurcan Tuncbag
Summary: Neurodevelopmental disorders (NDDs) and cancer have similarities in terms of proteins, pathways, and mutations, but have different clinical symptoms. However, individuals with NDDs have a higher likelihood of developing cancer later on. This review explores how shared features can result in different medical conditions and why having an NDD first can increase the chances of malignancy.
BIOPHYSICAL REVIEWS
(2023)
Meeting Abstract
Immunology
Mate Posta, Daniel Gyorffy, Peter Kiraly, Beata Hargitai, Orsolya Oravecz, Agnes Zvara, Laszlo Puskas, Andras Szilagyi, Petronella Hupuczi, Nandor Acs, Zoltan Papp, Nandor G. Than
JOURNAL OF REPRODUCTIVE IMMUNOLOGY
(2023)
Article
Genetics & Heredity
Bengi Ruken Yavuz, M. Kaan Arici, Habibe Cansu Demirel, Chung-Jung Tsai, Hyunbum Jang, Ruth Nussinov, Nurcan Tuncbag
Summary: Epidemiological studies show that individuals with neurodevelopmental disorders are more likely to develop certain types of cancer. While these disorders and cancer share proteins, pathways, and mutations, they differ in clinical outcomes. The key factor determining clinical outcome is signaling strength, with strong signaling promoting cell proliferation in cancer and moderate signaling affecting differentiation in neurodevelopmental disorders.
NPJ GENOMIC MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Ruth Nussinov, Yonglan Liu, Wengang Zhang, Hyunbum Jang
Summary: The propensities of protein conformations can predict cell function and suggest drug efficiency.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Ruth Nussinov, Yonglan Liu, Wengang Zhang, Hyunbum Jang
Summary: The sequence-structure-function paradigm in molecular biology has been updated to include the concept of conformational ensembles, recognizing that proteins are dynamic and constantly transitioning between different conformational states. The number and stability of these states are crucial for protein function. Understanding conformational propensities is essential for studying diverse systems and can provide insights into the dynamics of protein ensembles in cells.
RSC CHEMICAL BIOLOGY
(2023)