Article
Biochemical Research Methods
Lu-Chi Liu, Ming-Yang Ho, Bo-Han Su, San-Yuan Wang, Ming-Tsung Hsu, Yufeng J. Tseng
Summary: The PanGPCR system utilizes a library of experimentally determined crystal structures to predict potential GPCR targets, helping users to identify appropriate drug targets, determine repurposing potential, and predict potential side effects.
Review
Biochemistry & Molecular Biology
Preethi C. Karnam, Sergey A. Vishnivetskiy, Vsevolod V. Gurevich
Summary: Arrestins are a small family of proteins that bind G protein-coupled receptors (GPCRs) with high affinity to active phosphorylated GPCRs. They must have two sensors, which detect receptor-attached phosphates and the active receptor conformation independently, enabling transition into a high-affinity receptor-binding state. This transition involves a global conformational rearrangement that stabilizes the complex by bringing additional elements of the arrestin molecule in contact with a GPCR.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
J. D. Gross, D. W. Kim, Y. Zhou, D. Jansen, L. M. Slosky, N. B. Clark, C. R. Ray, X. Hu, N. Southall, A. Wang, X. Xu, E. Barnaeva, W. C. Wetsel, M. Ferrer, J. J. Marugan, M. G. Caron, L. S. Barak, K. Toth
Summary: This study discovered a novel GHSR(1a) agonist called N8279, which exhibits strong selectivity for G protein signaling, providing potential for treating disorders of disrupted dopamine homeostasis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Ioannis Mantas, Marcus Saarinen, Zhi-Qing David Xu, Per Svenningsson
Summary: This review discusses the differences between traditional and atypical antidepressants, highlighting the potential for faster and more effective antidepressant actions through interaction with GPCRs. It also explores the role of GPCRs in regulating the pathophysiology of MDD and the therapeutic potential of novel GPCR targets. Recent advances in understanding GPCR pharmacology and structure are highlighted as potential avenues for drug development.
MOLECULAR PSYCHIATRY
(2022)
Article
Biochemistry & Molecular Biology
Lukas Zell, Alina Bretl, Veronika Temml, Daniela Schuster
Summary: Different dopamine receptor subtypes are involved in various conditions, and this study identified novel ligands with high affinity and selectivity for D2R/D3R. In vitro experiments and in silico analysis were used to rationalize the ligands' selectivity and interaction with secondary binding pockets. This research contributes to the understanding of structural motifs responsible for DR subtype selectivity and can aid drug development in D2R/D3R-associated pathologies.
Review
Cell Biology
Gavin P. Schmitz, Bryan L. Roth
Summary: This article discusses the possibility of new transformative therapeutics for neuropsychiatric disorders by specifically targeting known and understudied GPCRs. Taking psychedelic drugs that target serotonin receptors as an example, recent insights into the structure, function, signaling, and cell biology of these receptors have led to potentially novel therapeutics. It also explores the potential of nonpsychedelic 5-HT2A receptor agonists as safe and rapidly acting antidepressants, and examines understudied and orphan GPCRs using the MRGPR family of receptors as an example.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2023)
Review
Pharmacology & Pharmacy
V. Marcel Alavi
Summary: The OMA1 protease in the mitochondrial inner membrane has potential as a drug target for complex diseases in the elderly. Its activation is related to cellular stress and apoptosis, and its inhibition can delay or prevent apoptosis in animal models. Understanding OMA1's structure and regulation is still limited, and technical challenges in OMA1 drug screens need to be addressed. Potent OMA1 inhibitors hold promise as a new class of cytoprotective medicines for disorders influenced by dysfunctional mitochondria.
PHARMACOLOGICAL RESEARCH
(2022)
Review
Pharmacology & Pharmacy
Austen B. Casey, Meng Cui, Raymond G. Booth, Clinton E. Canal
Summary: This review discusses the importance of blockade and activation of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) in the treatment of psychiatric disorders, and the limitations and strengths of currently available selective 5-HT2AR antagonists.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Kate A. Stafford, Brandon M. Anderson, Jon Sorenson, Henry van den Bedem
Summary: This paper introduces a deep learning-based approach, AtomNet PoseRanker (ANPR), to improve the quality of docking poses in virtual high-throughput screening (vHTS). Unlike traditional methods, ANPR can handle the dynamic nature of proteins, thus improving the accuracy of docking results.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Review
Biochemistry & Molecular Biology
Mansour Haddad, Federica Cherchi, Mohammad Alsalem, Yousef M. Al-saraireh, Saba Madae'en
Summary: This review presents new findings on the role of adenosine and its receptors in neuropathic and inflammatory pain. Adenosine receptor ligands have shown promising efficacy and safety in clinical research and could be used as therapeutic targets for various pain disorders. The review also discusses the latest studies on adenosine receptor ligands in different pain models and the potential of newly synthesized allosteric adenosine receptor modulators.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Chisato Kanai, Enzo Kawasaki, Ryuta Murakami, Yusuke Morita, Atsushi Yoshimori
Summary: This study explores the application of chemical genomics-based virtual screening (CGBVS) in predicting ligands for orphan targets, with results showing that protein descriptors using Multiple Sequence Alignment (MSA) performed well in overall prediction accuracy. It was also found that the accuracy of ligand prediction depends on the amount of ligand information related to GPCRs associated with the target.
Review
Physiology
Andrew F. Russo, Debbie L. Hay
Summary: Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. It acts through various receptors and is associated with disease states such as migraine. Therapeutics targeting the CGRP axis have shown success in bench-to-bedside translation. This review provides a comprehensive overview of CGRP's regulation, expression, physiological actions, and potential therapeutic targeting in various systems and diseases.
PHYSIOLOGICAL REVIEWS
(2023)
Review
Biochemistry & Molecular Biology
Malgorzata Jaronczyk, Jaroslaw Walory
Summary: This review provides an overview of molecular targets for antidepressants in the central nervous system (CNS) and computer-based strategies for discovering novel compounds with antidepressant activity.
Article
Chemistry, Physical
Nabil F. Faruk, Xiangda Peng, Karl F. Freed, Benoit Roux, Tobin R. Sosnick
Summary: Predicting protein binding is a challenging problem in computational biophysics. While docking algorithms based on rigid protein models can achieve some success, accurately capturing the conformational changes during binding remains difficult. This study investigates the impact of flexibility on predictions of protein-protein complexes using the Upside folding model. The results show that allowing backbone flexibility is generally detrimental to docking performance, but in the case of co-folding of flexible loops, it can improve binding.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Review
Pharmacology & Pharmacy
Attila Egyed, Dora Judit Kiss, Gyorgy M. Keseru
Summary: G-protein coupled receptors (GPCRs) are important therapeutic targets, with class A receptors representing the largest group and having the highest number of validated drug targets. In addition to the orthosteric binding pocket, secondary binding pocket (SBP) located in the extracellular vestibule also plays a role in modulating the pharmacology of the receptors. SBP binders significantly contribute to the pharmacological profile of bitopic ligands.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Reed M. Stein, Hye Jin Kang, John D. McCorvy, Grant C. Glatfelter, Anthony J. Jones, Tao Che, Samuel Slocum, Xi-Ping Huang, Olena Savych, Yurii S. Moroz, Benjamin Stauch, Linda C. Johansson, Vadim Cherezov, Terry Kenakin, John J. Irwin, Brian K. Shoichet, Bryan L. Roth, Margarita L. Dubocovich
Editorial Material
Multidisciplinary Sciences
Brian Krumm, Bryan L. Roth
Editorial Material
Biochemistry & Molecular Biology
Brian Krumm, Bryan L. Roth
Article
Multidisciplinary Sciences
Tao Che, Justin English, Brian E. Krumm, Kuglae Kim, Els Pardon, Reid H. J. Olsen, Sheng Wang, Shicheng Zhang, Jeffrey F. Diberto, Noah Sciaky, F. Ivy Carroll, Jan Steyaert, Daniel Wacker, Bryan L. Roth
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M. White, Matthew J. O'Meara, Veronica V. Rezelj, Jeffrey Z. Guo, Danielle L. Swaney, Tia A. Tummino, Ruth Huttenhain, Robyn M. Kaake, Alicia L. Richards, Beril Tutuncuoglu, Helene Foussard, Jyoti Batra, Kelsey Haas, Maya Modak, Minkyu Kim, Paige Haas, Benjamin J. Polacco, Hannes Braberg, Jacqueline M. Fabius, Manon Eckhardt, Margaret Soucheray, Melanie J. Bennett, Merve Cakir, Michael J. McGregor, Qiongyu Li, Bjoern Meyer, Ferdinand Roesch, Thomas Vallet, Alice Mac Kain, Lisa Miorin, Elena Moreno, Zun Zar Chi Naing, Yuan Zhou, Shiming Peng, Ying Shi, Ziyang Zhang, Wenqi Shen, Ilsa T. Kirby, James E. Melnyk, John S. Chorba, Kevin Lou, Shizhong A. Dai, Inigo Barrio-Hernandez, Danish Memon, Claudia Hernandez-Armenta, Jiankun Lyu, Christopher J. P. Mathy, Tina Perica, Kala Bharath Pilla, Sai J. Ganesan, Daniel J. Saltzberg, Ramachandran Rakesh, Xi Liu, Sara B. Rosenthal, Lorenzo Calviello, Srivats Venkataramanan, Jose Liboy-Lugo, Yizhu Lin, Xi-Ping Huang, YongFeng Liu, Stephanie A. Wankowicz, Markus Bohn, Maliheh Safari, Fatima S. Ugur, Cassandra Koh, Nastaran Sadat Savar, Quang Dinh Tran, Djoshkun Shengjuler, Sabrina J. Fletcher, Michael C. O'Neal, Yiming Cai, Jason C. J. Chang, David J. Broadhurst, Saker Klippsten, Phillip P. Sharp, Nicole A. Wenzell, Duygu Kuzuoglu-Ozturk, Hao-Yuan Wang, Raphael Trenker, Janet M. Young, Devin A. Cavero, Joseph Hiatt, Theodore L. Roth, Ujjwal Rathore, Advait Subramanian, Julia Noack, Mathieu Hubert, Robert M. Stroud, Alan D. Frankel, Oren S. Rosenberg, Kliment A. Verba, David A. Agard, Melanie Ott, Michael Emerman, Natalia Jura, Mark von Zastrow, Eric Verdin, Alan Ashworth, Olivier Schwartz, Christophe D'Enfert, Shaeri Mukherjee, Matt Jacobson, Harmit S. Malik, Danica G. Fujimori, Trey Ideker, Charles S. Craik, Stephen N. Floor, James S. Fraser, John D. Gross, Andrej Sali, Bryan L. Roth, Davide Ruggero, Jack Taunton, Tanja Kortemme, Pedro Beltrao, Marco Vignuzzi, Adolfo Garcia-Sastre, Kevan M. Shokat, Brian K. Shoichet, Nevan J. Krogan
Article
Biochemistry & Molecular Biology
Reid H. J. Olsen, Jeffrey F. DiBerto, Justin G. English, Alexis M. Glaudin, Brian E. Krumm, Samuel T. Slocum, Tao Che, Ariana C. Gavin, John D. McCorvy, Bryan L. Roth, Ryan T. Strachan
NATURE CHEMICAL BIOLOGY
(2020)
Article
Neurosciences
Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Jin Nakahara, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto
NATURE NEUROSCIENCE
(2020)
Article
Biochemistry & Molecular Biology
Xi-Ping Huang, Terrence P. Kenakin, Shuo Gu, Brian K. Shoichet, Bryan L. Roth
Article
Biochemistry & Molecular Biology
Kuglae Kim, Tao Che, Ouliana Panova, Jeffrey F. DiBerto, Jiankun Lyu, Brian E. Krumm, Daniel Wacker, Michael J. Robertson, Alpay B. Seven, David E. Nichols, Brian K. Shoichet, Georgios Skiniotis, Bryan L. Roth
Article
Chemistry, Medicinal
Reed M. Stein, Ying Yang, Trent E. Balius, Matt J. O'Meara, Jiankun Lyu, Jennifer Young, Khanh Tang, Brian K. Shoichet, John J. Irwin
Summary: The enrichment of ligands compared to property-matched decoys is commonly used in docking library screens, but over-optimizing for enrichment alone can lead to false confidence in prospective performance. By adding decoys representing charge extrema and overall characteristics of the library being docked, one can sample molecules not represented by the ligands and property-matched decoys, improving the accuracy of future screening results.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Multidisciplinary Sciences
Tia A. Tummino, Veronica V. Rezelj, Benoit Fischer, Audrey Fischer, Matthew J. O'Meara, Blandine Monel, Thomas Vallet, Kris M. White, Ziyang Zhang, Assaf Alon, Heiko Schadt, Henry R. O'Donnell, Jiankun Lyu, Romel Rosales, Briana L. McGovern, Raveen Rathnasinghe, Sonia Jangra, Michael Schotsaert, Jean-Rene Galarneau, Nevan J. Krogan, Laszlo Urban, Kevan M. Shokat, Andrew C. Kruse, Adolfo Garcia-Sastre, Olivier Schwartz, Francesca Moretti, Marco Vignuzzi, Francois Pognan, Brian K. Shoichet
Summary: Phospholipidosis may be a shared mechanism underlying the antiviral activity of many repurposed drugs, and early detection and elimination of these effects can enable a focus on molecules with therapeutic potential.
Article
Biochemical Research Methods
Brian J. Bender, Stefan Gahbauer, Andreas Luttens, Jiankun Lyu, Chase M. Webb, Reed M. Stein, Elissa A. Fink, Trent E. Balius, Jens Carlsson, John J. Irwin, Brian K. Shoichet
Summary: Structure-based docking screens of compound libraries are common in early drug and probe discovery. Best practices and control calculations are outlined to evaluate docking parameters prior to undertaking a large-scale prospective screen.
Article
Multidisciplinary Sciences
Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping Huang, Hayarpi Torosyan, Dallas Bednarczyk, Steven Whitebread, Barun Bhhatarai, Guiqing Liang, Hong Jin, S. Nassir Ghaemi, Samuel Slocum, Katalin V. Lukacs, John J. Irwin, Ellen L. Berg, Kathleen M. Giacomini, Bryan L. Roth, Brian K. Shoichet, Laszlo Urban