Review
Biochemistry & Molecular Biology
Shafi Ullah Khan, Nafees Ahemad, Lay-Hong Chuah, Rakesh Naidu, Thet Thet Htar
Summary: G protein-coupled receptors (GPCRs) are the largest family of protein targets, with at least 500 members being therapeutic targets. G protein-coupled estrogen receptor-1 (GPER-1) has the ability in estrogen signaling and is considered a potential therapeutic target for estrogen-based cancers and other non-communicable diseases. However, the progress in understanding the structure and function of GPER-1 has been slow due to the limited availability of selective GPER-1 modulators.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Review
Chemistry, Medicinal
Shome S. Bhunia, Anil K. Saxena
Summary: Homology modeling in GPCRs is challenging due to the lack of template structures, making it difficult to achieve accurate models that can elucidate ligand-receptor interactions. However, incorporating active/inactive ligand information and inducing protein flexibility have helped improve the accuracy of homology modeling in GPCRs.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Mydirah Littlepage-Saunders, Michael J. Hochstein, Doris S. Chang, Kari A. Johnson
Summary: Dopamine transmission in the striatum is regulated by various G protein-coupled receptors (GPCRs) that bind neuromodulators, including dopamine itself. These GPCRs can modulate dopamine release by acting on different components of the dopaminergic circuitry and can have distinct effects on behavior and psychoactive drug actions. This review discusses the mechanisms by which GPCRs regulate dopaminergic transmission and their relevance to the effects of psychoactive drugs on physiology and behavior.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Preeti Jha, Shubhra Chaturvedi, Ruchika Bhat, Nidhi Jain, Anil K. Mishra
Summary: The 5HT1A receptor is crucial in the treatment of depression and anxiety disorders, and the developed homology model shows promise in designing high-affinity probes for these neurological disorders.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Multidisciplinary
Xiaojing Cong, Wenwen Ren, Jody Pacalon, Rui Xu, Lun Xu, Xuewen Li, Claire A. de March, Hiroaki Matsunami, Hongmeng Yu, Yiqun Yu, Jerome Golebiowski
Summary: This study investigated how the amino-acid sequences of olfactory receptors (ORs) encode diversified responses to various ligands. Using a proteochemometric model, the researchers were able to predict OR responses to odorants and discover new OR-ligand pairs. This approach will contribute to the mapping of OR-odorant interactions and the identification of orphan receptors.
ACS CENTRAL SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Simona Daniele, Simona Saporiti, Stefano Capaldi, Deborah Pietrobono, Lara Russo, Uliano Guerrini, Tommaso Laurenzi, Elham Ataie Kachoie, Luca Palazzolo, Vincenzo Russo, Maria Pia Abbracchio, Ivano Eberini, Maria Letizia Trincavelli
Summary: GPR17, a key regulator of myelination, is activated by endogenous ligands and pro-inflammatory molecules. This study investigates the structural and functional interactions between GPR17 and chemokine receptors CXCR2 and CXCR4. The results show that these receptors can form heterodimers and modulate intracellular cAMP levels. This cross-talk between receptors could impact the neuroinflammatory environment associated with demyelinating events.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Immunology
Amar Ajmal, Arif Mahmood, Chandni Hayat, Mohammed Ageeli Hakami, Bader S. Alotaibi, Muhammad Umair, Ashraf N. Abdalla, Ping Li, Pei He, Abdul Wadood, Junjian Hu
Summary: Monkeypox is a zoonotic disease caused by monkeypox virus, transmitted through respiratory droplets, skin lesions, and body fluids. The study aims to identify potential drugs using computational methods.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2023)
Article
Biochemical Research Methods
Brittany N. Thomas, Abby L. Parrill, Daniel L. Baker
Summary: G protein-coupled receptors (GPCR) are the largest family of cell surface receptors in vertebrates and play a crucial role in pharmaceutical development. This study compares the docking performance of ligands with different functions into different GPCR activation states. The results show that the docking performance can be estimated in advance based on the docking target structure activation states, with potential improvements through receptor conformational adjustments.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Multidisciplinary Sciences
Qiuyan Chen, Manolo Plasencia, Zhuang Li, Somnath Mukherjee, Dhabaleswar Patra, Chun-Liang Chen, Thomas Klose, Xin-Qiu Yao, Anthony A. Kossiakoff, Leifu Chang, Philip C. Andrews, John J. G. Tesmer
Summary: GRKs selectively phosphorylate activated GPCRs for desensitization, with a conserved region at the GRK N terminus playing a crucial role. Cryo-EM reconstructions revealed the binding mechanism between GRK1 and Rho*, providing insights into how a small family of protein kinases can recognize and be activated by numerous GPCRs.
Article
Environmental Sciences
Juliana F. Tisca, Karin dos Santos, Tomas B. Pessati, Flavia L. Zacchi, Fabiola S. Soares, Vanessa A. Oliveira, Maria J. A. F. Bebianno, Afonso C. D. Bainy, Guilherme Razzera
Summary: The study found that higher transcript levels of the C. gigas FABP2 gene were detected after exposure to sewage and pharmaceuticals. Through homology modeling and molecular docking, it was discovered that CgFABP2 showed a preference for palmitic acid and a preference for diclofenac among the tested pharmaceuticals. The results suggest that using circular dichroism and in silico assays could be valuable for ligand-binding screening in invertebrate model organisms.
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
(2021)
Article
Chemistry, Medicinal
Alessandro Nicoli, Franziska Haag, Patrick Marcinek, Ruiming He, Johanna Kreissl, Joerg Stein, Alessandro Marchetto, Andreas Dunkel, Thomas Hofmann, Dietmar Krautwurst, Antonella Di Pizio
Summary: With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs), but their structural characterization is poor. This study focuses on the characterization of the odorant receptor OR5K1 by identifying its cognate agonists and investigating its binding modes using AI-driven modeling and homology modeling. The obtained models provide insights into the differences in activity and structural variations. This refinement protocol can be applied to model the orthosteric binding site of ORs and GPCRs with low sequence identity.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Pharmacology & Pharmacy
Estefania Moreno, Nil Casajuana-Martin, Michael Coyle, Baruc Campos Campos, Ewa Galaj, Claudia Llinas del Torrent, Arta Seyedian, William Rea, Ning-Sheng Cai, Alessandro Bonifazi, Benjamin Floran, Zheng-Xiong Xi, Xavier Guitart, Vicent Casado, Amy H. Newman, Christopher Bishop, Leonardo Pardo, Sergi Ferre
Summary: This study provides evidence that heteromerization of G protein-coupled receptors (GPCRs), specifically dopamine D1 and D3 receptors, can influence the pharmacological properties of selective ligands. In vivo experiments support the involvement of D1R-D3R heteromers in the development of L-DOPA-induced dyskinesia in Parkinson's disease, suggesting the potential of targeting GPCR heteromers for drug development.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Pharmacology & Pharmacy
Stephen P. H. Alexander, Arthur Christopoulos, Anthony P. Davenport, Eamonn Kelly, Alistair Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Adam J. Pawson, Christopher Southan, Jamie A. Davies, Maria Pia Abbracchio, Wayne Alexander, Khaled Al-hosaini, Magnus Baeck, Nicholas M. Barnes, Ross Bathgate, Jean-Martin Beaulieu, Kenneth E. Bernstein, Bernhard Bettler, Nigel J. M. Birdsall, Victoria Blaho, Francois Boulay, Corinne Bousquet, Hans Braeuner-Osborne, Geoffrey Burnstock, Girolamo Calo, Justo P. Castano, KevinJ Catt, Stefania Ceruti, Paul Chazot, Nan Chiang, Bice Chini, Jerold Chun, Antonia Cianciulli, Olivier Civelli, Lucie H. Clapp, Rejean Couture, Zsolt Csaba, Claes Dahlgren, Gordon Dent, Khuraijam Dhanachandra Singh, Steven D. Douglas, Pascal Dournaud, Satoru Eguchi, Emanuel Escher, Edward J. Filardo, Tung Fong, Marta Fumagalli, Raul R. Gainetdinov, Marc de Gasparo, Craig Gerard, Marvin Gershengorn, Fernand Gobeil, Theodore L. Goodfriend, Cyril Goudet, Karen J. Gregory, Andrew L. Gundlach, Joerg Hamann, Julien Hanson, Richard L. Hauger, Debbie L. Hay, Akos Heinemann, Morley D. Hollenberg, Nicholas D. Holliday, Mastgugu Horiuchi, Daniel Hoyer, Laszlo Hunyady, Ahsan Husain, Adriaan P. IJzerman, Tadashi Inagami, Kenneth A. Jacobson, Robert T. Jensen, Ralf Jockers, Deepa Jonnalagadda, Sadashiva Karnik, Klemens Kaupmann, Jacqueline Kemp, Charles Kennedy, Yasuyuki Kihara, Takio Kitazawa, Pawel Kozielewicz, Hans-Juergen Kreienkamp, Jyrki P. Kukkonen, Tobias Langenhan, Katie Leach, Davide Lecca, John D. Lee, Susan E. Leeman, Jerome Leprince, Xaria X. Li, Tom Lloyd Williams, Stephen J. Lolait, Amelie Lupp, Robyn Macrae, Janet Maguire, Jean Mazella, Craig A. McArdle, Shlomo Melmed, Martin C. Michel, Laurence J. Miller, Vincenzo Mitolo, Bernard Mouillac, Christa E. Mueller, Philip Murphy, Jean-Louis Nahon, Tony Ngo, Xavier Norel, Duuamene Nyimanu, Anne-Marie Ocarroll, Stefan Offermanns, Maria Antonietta Panaro, Marc Parmentier, Roger G. Pertwee, Jean-Philippe Pin, Eric R. Prossnitz, Mark Quinn, Rithwik Ramachandran, Manisha Ray, Rainer K. Reinscheid, Philippe Rondard, G. Enrico Rovati, Chiara Ruzza, Gareth J. Sanger, Torsten Schoeneberg, Gunnar Schulte, Stefan Schulz, Deborah L. Segaloff, Charles N. Serhan, Leigh A. Stoddart, Yukihiko Sugimoto, Roger Summers, Valerie P. Tan, David Thal, Walter (Wally) Thomas, PieterB M. W. M. Timmermans, Kalyan Tirupula, Giovanni Tulipano, Hamiyet Unal, Thomas Unger, Celine Valant, Patrick Vanderheyden, David Vaudry, Hubert Vaudry, Jean-Pierre Vilardaga, Christopher S. Walker, Ji Ming Wang, Donald T. Ward, Hans-Juergen Wester, Gary B. Willars, Trent M. Woodruff, Chengcan Yao, Richard D. Ye
Summary: The Concise Guide to PHARMACOLOGY 2021/22 presents concise overviews of nearly 1900 human drug targets with an emphasis on selective pharmacology, along with links to a more detailed knowledgebase. It serves as a permanent, citable record for researchers, providing useful information in the field of pharmacology.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Biology
Oliver Fleetwood, Jens Carlsson, Lucie Delemotte
Summary: The study elucidated how ligands stabilize the conformation of G protein-coupled receptors by tuning protein microswitches, influencing the activation state of the signaling pathway. Ligand binding induces a shift of the receptor towards active-like states, and different ligands can induce similar conformational states.
Article
Microbiology
Janak Sunuwar, Rajeev K. Azad
Summary: Antimicrobial resistance poses a threat to global healthcare systems, but machine learning offers potential in uncovering novel resistance genes and aiding the development of more effective solutions.
Article
Biochemistry & Molecular Biology
Kiran S. Toti, Ryan G. Campbell, Hobin Lee, Veronica Salmaso, R. Rama Suresh, Zhan-Guo Gao, Kenneth A. Jacobson
Summary: Adenosine receptor (AR) ligands are being developed for the treatment of metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. Fluorescent antagonist ligands were synthesized and screened for their affinities and selectivity towards different AR subtypes, showing potential as live cell or in vivo imaging tools and/or therapies.
PURINERGIC SIGNALLING
(2023)
Book Review
Chemistry, Medicinal
Kenneth A. Jacobson
Review
Biochemistry & Molecular Biology
Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: Efforts to understand pharmacological differences between GPCR species homologues are generally not pursued in drug development. However, studying the pharmacological properties of the A(3) adenosine receptor (AR) is critical for understanding its biological functions. Pharmacological characterization of recombinant A(3)ARs from different species has been conducted.
PURINERGIC SIGNALLING
(2023)
Article
Neurosciences
Kenneth A. Jacobson, Balaram Pradhan, Zhiwei Wen, Asmita Pramanik
Summary: The discovery and clinical implementation of adenosine, P2Y and P2X receptor modulators have advanced significantly in the past 50 years. Although previous clinical trials of selective ligands have not been successful, there is now a renewed focus on new disease conditions and the development of more selective compounds, as well as the elucidation of new receptor and enzyme structures.
Article
Biochemistry & Molecular Biology
Cuiying Xiao, Oksana Gavrilova, Naili Liu, Sarah A. Lewicki, Marc L. Reitman, Kenneth A. Jacobson
Summary: Some drugs act on adenosine receptors (ARs) to produce effects, as demonstrated in mouse hypothermia experiments. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased adenosine-induced hypothermia, while two drugs (cannabidiol, canrenoate) did not cause hypothermia. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia through non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity, which was reduced in mice lacking ARs. Interestingly, the antidepressant amitriptyline caused amplified hypothermia in mice lacking ARs. These findings suggest potential repurposing of adenosine-modulating drugs based on their effects on AR activation.
PURINERGIC SIGNALLING
(2023)
Article
Biochemistry & Molecular Biology
Federica Cherchi, Martina Venturini, Giada Magni, Mirko Scortichini, Kenneth A. Jacobson, Anna Maria Pugliese, Elisabetta Coppi
Summary: Recent studies have focused on the analgesic effects of adenosine and its receptors in chronic pain models. The A(3)AR receptor subtype has been found to reduce pro-nociceptive N-type Ca2+ channels, leading to inhibition of post inflammatory visceral hypersensitivity. This study investigates the effect of a previously reported irreversible A(3)AR agonist, ICBM, on Ca2+ currents in rat DRG neurons. The findings suggest that covalent A(3)AR agonists such as ICBM may offer a longer-lasting and more efficient strategy for chronic pain control compared to reversible A(3)AR agonists, but further pre-clinical studies are needed to address potential limitations and adverse effects.
PURINERGIC SIGNALLING
(2023)
Editorial Material
Pharmacology & Pharmacy
Francisco Ciruela, Kenneth A. Jacobson
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Zhan-Guo Gao, Ian M. Levitan, Asuka Inoue, Qiang Wei, Kenneth A. Jacobson
Summary: Protein kinase C (PKC) isoforms can enhance A(2B) adenosine receptor (AR)-mediated cAMP accumulation through activation by phorbol 12-myristate 13-acetate (PMA), but do not enhance beta(2)-adrenergic receptor-mediated cAMP accumulation. PKC activation can also induce cAMP accumulation by activating A(2B)AR with high or low E-max. These findings are important for understanding the functions of A(2B)AR and PKC.
Article
Biochemistry & Molecular Biology
Qasim Shah, Zahid Hussain, Bilal Ahmad Khan, Kenneth A. Jacobson, Jamshed Iqbal
Summary: The study investigates the potency of P2X7 receptor antagonists and their relationship with cancer, revealing five compounds with strong selective inhibitory effects. These compounds exhibit varying cell viability and induction of apoptosis in transfected and non-transfected cell lines.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Maggie M. Calkins, Marko S. Ivancich, Hailey A. Bock, Ryan G. Campbell, Sarah A. Lewicki, Eric Chen, Zhan-Guo Gao, John D. Mccorvy, Kenneth A. Jacobson
Summary: Derivatives of (N)-Methanocarba adenosine were modified to target 5-HT2B serotonin receptors as antagonists, showing affinity enhancement with the bicyclic ring system. Compound 43 (MRS7925) exhibited potential for anti-fibrotic therapy due to its affinity and moderate 5-HT2BR binding selectivity. The compounds also demonstrated dual action as 5-HT2B antagonists and A(1)AR agonists.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Katarina Mihajlovic, Marija Adzic Bukvic, Milorad Dragic, Mirko Scortichini, Kenneth A. Jacobson, Nadezda Nedeljkovic
Summary: In this in vitro study, three novel cytosine-derived alpha,beta-methylene diphosphonates (MRS4598, MRS4552, and MRS4602) were tested for their potency in inhibiting CD73 activity and attenuating reactive astrocyte phenotype. The results showed that all compounds exhibited concentration-dependent inhibition of CD73 activity with high inhibitory potency and binding capacity. Among them, MRS4598 was the most effective in inhibiting CD73 activity and inducing reactive astrocyte phenotype inhibition, making it a promising tool for the treatment of neurodegeneration and neuroinflammation.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Zhiwei Wen, Asmita Pramanik, Sarah A. Lewicki, Young-Hwan Jung, Zhan-Guo Gao, John C. R. Randle, Chunxia Cronin, Zhoumou Chen, Luigino A. Giancotti, Gregory S. Whitehead, Bruce T. Liang, Sylvie Breton, Daniela Salvemini, Donald N. Cook, Kenneth A. Jacobson
Summary: P2Y(14) receptor is activated by extracellular UDP-glucose, promoting inflammation in various tissues. Selective P2Y(14)R antagonists could be useful for inflammatory and metabolic diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Hai-Jun Zhang, Michal Ociepa, Molhm Nassir, Bin Zheng, Sarah A. Lewicki, Veronica Salmaso, Helay Baburi, Jessica Nagel, Salahuddin Mirza, Haneen Al-Hroub, Beatriz Bueschbell, Olga Perzanowska, Ziqin Lin, Michael A. Schmidt, Martin D. Eastgate, Kenneth A. Jacobson, Christa E. Mueller, Joanna Kowalska, Jacek Jemielity, Phil S. Baran
Summary: Nucleoside diphosphates and triphosphates have a profound impact on biochemistry, but their usage as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hindered by their rapid metabolism in the body. This study demonstrates the development of a modular, reagent-based platform that allows the stereocontrolled and scalable synthesis of pure stereoisomers of nucleoside thioisosteres, which can have significant effects on ligand-receptor interactions.
Article
Chemistry, Medicinal
Eline Pottie, R. Rama Suresh, Kenneth A. Jacobson, Christophe P. Stove
Summary: This study aimed to explore inverse agonism at A(3)AR using two engineered cell lines and NanoBiT technology. The previously established inverse agonist PSB-10 showed inverse agonism in one assay but not in another. Further experiments confirmed the specificity and reversibility of this observation. Evaluation of presumed neutral antagonists revealed their concentration-dependent inverse agonism in the A(3)AR-βarr2 recruitment assay.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Courtney L. Fisher, Veronica Salmaso, Tina C. Wan, Ryan G. Campbell, Eric Chen, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: (N)-Methanocarba adenosine derivatives were modified to form macrocyclic A(3) adenosine receptor agonists. These macrocycles retained affinity and had a spatially proximal orientation on the receptor. C2-Arylethynyl-linked macrocycle 19 showed higher selectivity for A(3) adenosine receptor compared to 2-ether-linked macrocycle 12.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)