Article
Biochemistry & Molecular Biology
Canyong Guo, Lingyun Yang, Zhijun Liu, Dongsheng Liu, Kurt Wuthrich
Summary: Eight hundred and twenty-six human G protein-coupled receptors (GPCRs) play a significant role in mediating the actions of hormones, neurotransmitters, and drugs. Studying the structure and dynamics of GPCRs in lipid bilayer environments is crucial for understanding their functionality and developing new drugs. This study incorporates the A(2A) adenosine receptor into lipid nanodiscs, providing a detergent-free environment for structural studies using NMR. The findings demonstrate the stability and mimicry of the lipid nanodisc and LMNG/CHS micelles in preserving the overall fold and local structure of the receptor.
Article
Biochemical Research Methods
Mukuo Wang, Shujing Hou, Yu Wei, Dongmei Li, Jianping Lin
Summary: Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system. Dual adenosine A(1)/A(2A) receptor antagonists provide a possible effective therapy that can simultaneously solve motor symptoms and nonmotor symptoms in the medical treatment of PD. In this study, a multistage virtual screening approach involving deep learning, pharmacophore models, and molecular docking methods identified two 1,2,4-triazole derivatives as dual adenosine A(1) and A(2A) receptor antagonists. The results of molecular dynamics (MD) simulations showed strong binding interactions between the adenosine A(1)/A(2A) receptors and the compounds.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Neurosciences
Olamide E. Adebiyi, Margaret S. Bynoe
Summary: This study investigates the role of A(1) and A(2A) adenosine receptors in regulating oligodendrocyte precursor cells and myelinating oligodendrocytes in the demyelinated hippocampus. It found that the absence of A(1) and A(2A) adenosine receptors affects spatial learning and memory, and has an impact on hippocampal demyelination and cell apoptosis.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sergey A. Vishnivetskiy, Elizabeth K. Huh, Preethi C. Karnam, Samantha Oviedo, Eugenia Gurevich, Vsevolod V. Gurevich
Summary: Arrestins preferentially bind phosphorylated G protein-coupled receptors (GPCRs) through their conserved middle loop, which directly interacts with the bound GPCR. Mutagenesis studies reveal that the middle loop primarily acts as a suppressor of binding to non-preferred forms of the receptor. Certain mutations in the middle loop enhance the binding to unphosphorylated light-activated rhodopsin, making them potential candidates for improving phosphorylation-independent arrestins. However, enhanced forms of arrestin do not bind GPCRs exactly like the wild-type protein, indicating the need for caution when interpreting the structures of arrestin-receptor complexes with different enhanced arrestin mutants and reengineered receptors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Pharmacology & Pharmacy
Harmandeep Kaur, Veera Ganesh Yerra, Sri Nagarjun Batchu, Duc Tin Tran, M. D. Golam Kabir, Youan Liu, Suzanne L. Advani, Phelopater Sedrak, Laurette Geldenhuys, Karthik K. Tennankore, Penelope Poyah, Ferhan S. Siddiqi, Andrew Advani
Summary: In this study, a transcriptional profile of activated kidney fibroblasts and the GPCRs they express was established in mouse models of kidney disease. The marker Tcf21 and the GPCRs Adgra2 and S1pr3 were found to be highly expressed in these activated fibroblasts. This research provides new insights into potential therapeutic targets for treating CKD.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemical Research Methods
Balaji Wamanrao Matore, Purusottam Banjare, Jagadish Singh, Partha Pratim Roy
Summary: Designing selective drug candidates for structurally similar targets is a challenging task. This study aimed to explore the selectivity modeling of pyridine and pyrimidine scaffold towards highly homologous targets CYP11B1 and CYP11B2 enzymes using computational methods. Molecular docking and QSAR analysis revealed the importance of structural features and functional groups for selectivity and highlighted the differentiating amino acid residues for ligand selectivity. These findings will be useful for designing selective CYP11B1/CYP11B2 inhibitors.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Immunology
Yajia Cheng, Peipei Cao, Chao Geng, Xiaoqi Chu, Yuhao Li, Jianlin Cui
Summary: Photoreceptor degeneration is a critical event in various retinal diseases, but there is currently no curative treatment available. This study showed that the A2AR antagonist SCH58261 protected photoreceptors by inhibiting inflammation, apoptosis, and autophagy at the early stage of degeneration.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
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
Chemistry, Medicinal
Elena Cichero, Valeria Francesconi, Beatrice Casini, Monica Casale, Evgeny Kanov, Andrey S. Gerasimov, Ilya Sukhanov, Artem Savchenko, Stefano Espinoza, Raul R. Gainetdinov, Michele Tonelli
Summary: This study used computational methods to identify structural differences between TAAR1 and α2-ADR and design selective TAAR1 agonists. It found that guanfacine could be a potential TAAR1-targeting compound with nanomolar activity in vitro. In vivo experiments showed that guanfacine could decrease locomotor activity in dopamine transporter knockout rats.
Review
Biochemistry & Molecular Biology
Efpraxia Tzortzini, Antonios Kolocouris
Summary: Most membrane lipids interact with GPCRs structures and modulate their function. PIP2 and cholesterol have an impact on the conformational equilibria of the A(2A) adenosine receptor.
Article
Oncology
Takao Kamai, Toshiki Kijima, Toyonori Tsuzuki, Akinori Nukui, Hideyuki Abe, Kyoko Arai, Ken-Ichiro Yoshida
Summary: In patients with metastatic RCC, high expression of A2AR in primary tumors was associated with metastatic profiles. Patients treated with anti-PD-1 antibody or a combination of anti-PD-1 and anti-CTLA4 antibodies, or anti-VEGF agents showed better response and longer overall survival if the primary tumor had higher PD-L1 expression and lower A2AR expression.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2021)
Review
Chemistry, Medicinal
Hyeonyeong Im, Ji-Hyun Park, Seowoo Im, Juhyeong Han, Kyungmin Kim, Yun-Hee Lee
Summary: The high incidence of obesity has led to an increased need to discover new therapeutic targets. Recent research has shown that G-protein coupled receptors (GPCRs) could be potential therapeutic targets to regulate adipose tissue metabolism.
ARCHIVES OF PHARMACAL RESEARCH
(2021)
Article
Chemistry, Medicinal
Friederike Wunsch, Trung Ngoc Nguyen, Gerhard Wolber, Marcel Bermudez
Summary: Fingolimod is an approved drug for treating multiple sclerosis by modulating sphingosine-1-phosphate receptors (S1PR) through its prodrug fingolimod-1-phosphate (F1P). S1PR3-related side effects led to the development of S1PR1,5-selective drugs. This study combines molecular dynamics simulations and dynamic pharmacophores to analyze the structural reasons for selectivity, contributing to the understanding of S1PR subtype selectivity.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Medicinal
Jon Kyle Awalt, Anh T. N. Nguyen, Tim J. Fyfe, Bui San Thai, Paul J. White, Arthur Christopoulos, Manuela Joerg, Lauren T. May, Peter J. Scammells
Summary: The adenosine A(1) receptor is a therapeutic target for cardioprotection during myocardial ischemia and reperfusion injury. However, clinical translation of A(1)R agonists is hindered by dose-limiting adverse effects. The bitopic agonist VCP746, consisting of an adenosine pharmacophore linked to an allosteric moiety, has shown promising results in stimulating cardioprotective A(1)R signaling effects without unwanted bradycardia. This study investigates the structure-activity relationships of VCP746 and identifies the most potent A2BR agonist to date.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Gastroenterology & Hepatology
Willemien van Zwol, Antoine Rimbert, Justina C. Wolters, Marieke Smit, Vincent W. Bloks, Niels J. Kloosterhuis, Nicolette C. A. Huijkman, Mirjam H. Koster, Umesh Tharehalli, Simon M. de Neck, Colin Bournez, Marceline M. Fuh, Jeroen Kuipers, Sujith Rajan, Alain de Bruin, Henry N. Ginsberg, Gerard J. P. van Westen, M. Mahmood Hussain, Ludger Scheja, Joerg Heeren, Philip Zimmerman, Bart van de Sluis, Jan Albert Kuivenhoven
Summary: By analyzing the co-expression of genes, we identified the small leucine-rich protein 1 (SMLR1) as a player in the VLDL biogenesis pathway. The loss of hepatic SMLR1 in mice leads to hepatic steatosis, reduced VLDL secretion, providing protection against hyperlipidemia and atherosclerosis.
Article
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
Summary: CCR2, a G protein-coupled receptor, is involved in various cancer-related processes. Mutations in CCR2 were investigated for their impact on receptor functionality and antagonist binding. Most mutants showed a decrease in G protein activation in response to the main ligand, while orthosteric antagonist binding was affected by specific mutations and allosteric antagonist binding was completely abolished in certain mutants. Considering CCR2 as a potential drug target in cancer, the negative effects of these mutations on receptor functionality and drug development should be considered.
BIOCHEMICAL PHARMACOLOGY
(2023)
Correction
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sohvi Luukkonen, Helle W. van den Maagdenberg, Michael T. M. Emmerich, Gerard J. P. van Westen
Summary: The factors determining a drug's success are diverse, making drug design a multi-objective optimisation problem. With the emergence of machine learning and optimisation methods, there has been a rapid increase in developments and applications in the field of multi-objective compound design. Population-based metaheuristics and deep reinforcement learning are commonly used methods, but conditional learning methods are gaining popularity. This article provides a brief overview of the field and the latest innovations.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Martin Sicho, Sohvi Luukkonen, Helle W. van den Maagdenberg, Linde Schoenmaker, Olivier J. M. Bequignon, Gerard J. P. van Westen
Summary: The discovery of new molecules with desirable properties is a classic challenge in medicinal chemistry. Machine learning has greatly advanced de novo drug design tools, but there is a lack of user-friendly and customizable resources. In this application note, we present DrugEx, a versatile open-source software package for multiobjective reinforcement learning. It includes multiple generator architectures, scoring tools, and optimization methods, and can be used via command line interface or graphical user interface GenUI. The DrugEx package is publicly available at https://github.com/CDDLeiden/DrugEx.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Sohvi Luukkonen, Erik Meijer, Giovanni A. Tricarico, Johan Hofmans, Pieter F. W. Stouten, Gerard J. P. van Westen, Eelke B. Lenselink
Summary: Protein kinases are a protein family with important roles in complex diseases. They have ATP binding sites that can be targeted to create multitarget drugs. Multitask deep learning models outperform single-task deep learning and tree-based models for protein kinase activity prediction.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: In this study, a computational screening pipeline was developed to find new inhibitors for the NET protein. A data-driven approach was used to diversify the chemical space and select optimal proteins to model for NETs. A proteochemometric model was created and applied to an extensive compound database, resulting in the identification of five potential hit compounds with promising inhibitory potencies toward NET.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Xuhan Liu, Kai Ye, Herman W. T. van Vlijmen, Adriaan P. IJzerman, Gerard J. P. van Westen
Summary: In the field of rational drug design, deep learning methods have been employed to generate reliable drug molecules based on new design principles. The Transformer model is used to generate molecular structures, resulting in more effective drug design. The method allows users to design drug molecules according to their specific needs.
JOURNAL OF CHEMINFORMATICS
(2023)
Article
Infectious Diseases
Colin Bournez, Martijn Riool, Leonie de Boer, Robert A. Cordfunke, Leonie de Best, Remko van Leeuwen, Jan Wouter Drijfhout, Sebastian A. J. Zaat, Gerard J. P. van Westen
Summary: To combat infection, host organisms possess defense peptides, including antimicrobial peptides (AMPs), which can target a wide range of pathogenic microorganisms. Researchers have developed a machine learning model called CalcAMP that can predict the activity of AMPs. This model can help in identifying potential short AMPs quickly, which can be an effective solution to the growing issue of multi-drug resistance. CalcAMP is based on a new data set constructed from available public data on AMPs and experimental antimicrobial activities, and it can predict activity against both Gram-positive and Gram-negative bacteria.
Article
Chemistry, Medicinal
Bert L. H. Beerkens, Inge M. Snijders, Joep Snoeck, Rongfang Liu, Anton T. J. Tool, Sylvia E. Le Devedec, Willem Jespers, Taco W. Kuijpers, Gerard J. P. van Westen, Laura H. Heitman, Adriaan P. IJzerman, Daan van der Es
Summary: This article describes the development of a new probe for detecting human A(3)AR, which has been validated through radioligand displacement, SDS-PAGE, confocal microscopy, and flow cytometry experiments. The probe is expected to be of great significance for future studies on the expression and function of A(3)AR in pathologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: This study developed a computational screening pipeline to identify new inhibitors for the high-affinity norepinephrine transporter (NET). By using the chemical space of related proteins, a data-driven approach was used to diversify the known chemical space for NET modeling. The final model, created through a two-step approach, predicted 46 chemically diverse candidates, of which five compounds showed promising inhibitory potency towards NET in experimental assays.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Bert L. H. Beerkens, Cagla Koc, Rongfang Liu, Bogdan I. Florea, Sylvia E. Le Devedec, Laura H. Heitman, Adriaan P. IJzerman, Daan Van Der Es
Summary: G protein-coupled receptors (GPCRs) have long been recognized as attractive drug targets, but many aspects of GPCR signaling remain poorly understood due to the difficulties encountered in studying them. In this study, we have developed an affinity-based probe for a prototype GPCR, the adenosine A(1) receptor (A(1)AR), and conducted various biochemical assays to evaluate its efficacy.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Qiuyu Liu, Wanda van der Stel, Vera E. van der Noord, Hanneke Leegwater, Bircan Coban, Kim Elbertse, Joannes T. M. Pruijs, Olivier J. M. Bequignon, Gerard van Westen, Sylvia E. Le Devedec, Erik H. J. Danen
Summary: Hypoxia triggers HIF1 stabilization in luminal and basal A triple negative breast cancer cells. High throughput targeted RNA sequencing reveals overlapping and distinct target genes being modulated in these subtypes. Hypoxia induces phosphorylation of TAZ at Ser89 in basal A cells, leading to cytoplasmic sequestration of TAZ(Ser89). Hypoxia attenuates growth of basal A cells and diminishes the effect of verteporfin, a disruptor of YAP/TAZ-TEAD-mediated transcription.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)