Article
Biochemical Research Methods
P. Castleman, G. Szwabowski, D. Bowman, J. Cole, A. L. Parrill, D. L. Baker
Summary: This study evaluated the impact of key decisions in pharmacophore modeling for GPCR with limited known ligands, demonstrating that pharmacophore models can be effectively applied to GPCR targets with limited ligand data availability.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Chemistry, Medicinal
Rina Kwag, Jieon Lee, Doyoung Kim, Haeun Lee, Miyoung Yeom, Jiwan Woo, Yakdol Cho, Hak Joong Kim, Jeongjin Kim, Gyochang Keum, Byungsun Jeon, Hyunah Choo
Summary: By designing and synthesizing a series of compounds and evaluating their activities and selectivities, it was found that one compound showed good binding affinity and selectivity for 5-HT7R, exhibiting a G protein-biased antagonistic effect. The compound demonstrated inhibitory effects on self-grooming behavior in transgenic mice, indicating that 5-HT7R may be a potential therapeutic target for treating stereotypical behaviors in autism spectrum disorder.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Stefanie Kampen, Duc Duy Vo, Xiaoqun Zhang, Nicolas Panel, Yunting Yang, Mariama Jaiteh, Pierre Matricon, Per Svenningsson, Jose Brea, Maria Isabel Loza, Jan Kihlberg, Jens Carlsson
Summary: This study presents a structure-based strategy to design compounds with dual-target properties, which can both antagonize the A(2A) adenosine receptor and activate the D-2 dopamine receptor, showing promising potential as anti-parkinson drugs.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Biochemistry & Molecular Biology
Jace Jones-Tabah
Summary: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the deterioration of dopaminergic neurons and motor impairment. Although there is no cure for PD, dopamine replacement therapies like L-DOPA can alleviate motor symptoms. However, non-motor symptoms and the progression of neurodegeneration still lack effective treatments. This review focuses on G protein-coupled receptors (GPCRs) as potential targets for treating PD and discusses various therapeutic strategies.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Krzysztof Jozwiak, Anita Plazinska
Summary: Studies on different receptors belonging to class A of GPCRs reveal specific molecular mechanisms behind ligand directed signaling, including the role of important residues, the impact of ligand structural features on signaling, and the key interactions between ligands and receptors.
Article
Biochemistry & Molecular Biology
Alessandra de Felice, Simone Aureli, Vittorio Limongelli
Summary: GPCRs, the largest human membrane receptor family, are important drug targets and CPG is a new computational approach that can help analyze cross-activity of drugs towards different GPCR receptors, aiding in the design of more selective compounds.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Multidisciplinary Sciences
Ashley Ryan Vidad, Stephen Macaspac, Ho Leung Ng
Summary: This study successfully predicts ligand binding sites in class A GPCRs using a combination of surface conservation and docking information, including crystallized GPCRs and homology models, and can be applied to structurally uncharacterized GPCRs. The predicted sites match those found in other independent modeling studies, and ConDockSite overcomes errors introduced from physics-based scoring functions and homology modeling.
Article
Chemistry, Multidisciplinary
Mark T. Agasid, Lars Sorensen, Leonhard H. Urner, Jun Yan, Carol Robinson
Summary: The use of mass spectrometry to study G protein-coupled receptors has revealed insights into sodium binding and ligand-induced changes, providing valuable information for understanding GPCR function.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Review
Engineering, Biomedical
Yuhong Jiang, Yuke Li, Xiujuan Fu, Yue Wu, Rujing Wang, Mengnan Zhao, Canquan Mao, Sanjun Shi
Summary: The translation article introduces the interaction between G protein-coupled receptors (GPCRs) and nanotechnology, as well as how nanotechnology can improve the efficacy and safety of GPCR-related drugs. Nanotechnology can encapsulate GPCR ligands to construct synthetic nano-GPCRs and precisely initiate sustained endosomal signal transduction through nanoparticles. Moreover, nanoparticles can enhance the potency of delivery systems by actively targeting specific cells through ligand-receptor binding and receptor-dependent endocytosis.
ACTA BIOMATERIALIA
(2023)
Review
Chemistry, Medicinal
Joshua W. Conner, Daniel P. Poole, Manuela Jorg, Nicholas A. Veldhuis
Summary: This review addresses the key challenges, synthesis approaches, and structure-activity relationships in recent fluorescent small molecule studies for GPCRs, and discusses the advantages of using high-resolution GPCR structures to inform conjugation strategies.
FUTURE MEDICINAL CHEMISTRY
(2021)
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
Chemistry, Medicinal
Thanigaimalai Pillaiyar, Francesca Rosato, Monika Wozniak, Jeremy Blavier, Maelle Charles, Celine Laschet, Thales Kronenberger, Christa E. Mueller, Julien Hanson
Summary: This study identified a selective GPR27 agonist and a series of new derivatives and analogs, including potent agonists with higher efficacies than the lead compound. Docking studies predicted the putative binding site and interactions of an agonist with GPR27, providing important new tools for further characterizing the (patho)physiological roles of GPR27.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
Xin-heng He, Chong-zhao You, Hua-liang Jiang, Yi Jiang, H. Eric Xu, Xi Cheng
Summary: G protein-coupled receptors (GPCRs) are important drug targets that play crucial roles in various physiological processes. Although extensive efforts have been made in the field of structural biology, a significant number of GPCR structures remain unsolved due to their structural instability. Recently, AlphaFold2 has been developed as a tool to predict the structure models of GPCRs and other functionally important proteins. However, our evaluation reveals several differences between the predicted models and experimental structures, such as the assembly of domains, shape of ligand-binding pockets, and conformation of binding interfaces. These differences hinder the use of predicted structure models in functional studies and structure-based drug design, where reliable high-resolution structural information is required.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Biochemistry & Molecular Biology
Anju Sharma, Rajnish Kumar, Pritish Varadwaj
Summary: This study comprehensively investigates the interactions between olfactory receptors (ORs) and odorants, and suggests potential odor percepts for ORs through the development of a human OR-OR network. The research findings reveal distinct characteristics and molecular interactions between odorants and specific ORs, contributing to a better understanding of the complex issue of odor perception.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Pharmacology & Pharmacy
Ratul Bhowmik, Ajay Manaithiya, Bharti Vyas, Ranajit Nath, Kamal A. Qureshi, Seppo Parkkila, Ashok Aspatwar
Summary: This article discusses various techniques used in tuberculosis drug discovery, including computational approaches. It introduces different databases, methods, approaches, and software used in conducting QSAR, pharmacophore modeling, and molecular docking. The important molecules discovered using these computational approaches and drugs in clinical trials for tuberculosis are also discussed. Finally, the challenges and future perspectives of these techniques in drug discovery are summarized.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Physical
Maria Lbadaoui-Darvas, Giovanni Garberoglio, Katerina S. Karadima, M. Natalia D. S. Cordeiro, Athanasios Nenes, Satoshi Takahama
Summary: This comprehensive review explores methods and applications of molecular simulations of interfacial systems, providing detailed insights into techniques and challenges in solid and fluid surfaces. The review also summarizes methods for estimating macroscopic properties of interfaces and extracting information about fluctuating liquid surfaces, demonstrating their application in atmospheric science, material science, and biophysics. The main goals are to guide practical questions in software, force fields, and select appropriate analysis methods, while highlighting the potential for molecular simulations to advance our understanding in applied science.
MOLECULAR SIMULATION
(2023)
Article
Chemistry, Physical
Jose L. C. Fajin, M. Natalia D. S. Cordeiro
Summary: Ni-Cu catalysts are low cost, highly selective for CO2 and H-2 in methanol steam reforming, blocking the production of methane, CO, and coke. The mechanism of methanol steam reforming on Ni-Cu surfaces involves methanol decomposition followed by the water-gas shift reaction, with a minority route for direct CO2 formation. The Ni-Cu alloy suppresses methane and coke formation and has a high desorption barrier for CO species, avoiding its production.
Article
Chemistry, Medicinal
Michael Gonzalez-Durruthy, Riccardo Concu, Laura F. Osmari Vendrame, Mirkos Ortiz Martins, Ivana Zanella, Juan Manuel Ruso, Maria Natalia Dias Soeiro Cordeiro
Summary: This study combined molecular docking approaches and DFT ab initio simulations to investigate the key interactions of cyclodextrins (CDs) with potential pharmacological relevance and the multidrug resistance P-gp protein. The findings provide valuable insights into the CD docking mechanism and the role of P-gp in drug delivery.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2023)
Article
Engineering, Biomedical
Tiffany S. Pinho, Deolinda Silva, Jorge Cibrao Ribeiro, Ana Marote, Rui Lima, Salete J. Batista, Rita Melo, Clarisse Ribeiro, Cristiana B. Cunha, Irina S. Moreira, Senentxu Lanceros-Mendez, Antonio J. Salgado
Summary: This study focuses on the application of poled and coated PVDF films for neural differentiation and found that these films can induce neuronal differentiation under mechanical stimulation, which is further enhanced with a pre-coating step of poly-d-lysine and laminin.
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
(2023)
Article
Biochemistry & Molecular Biology
Riccardo Concu, Maria Natalia Dias Soeiro Cordeiro, Martin Perez-Perez, Florentino Fdez-Riverola
Summary: This study developed a novel multi-target machine learning (MTML) quantitative structure-activity relationship (QSAR) model for predicting interactions between different drugs and enzyme targets. The model was based on a large dataset of drug-enzyme pairs and used topological drug features and artificial neural network (ANN) multi-layer perceptron (MLP). The validated model showed an overall accuracy of over 96%. To maximize its diffusion, a public and accessible web-based tool was developed for users to make their own predictions.
Article
Biochemistry & Molecular Biology
Ana B. Caniceiro, Beatriz Bueschbell, Carlos A. V. Barreto, Antonio J. Preto, Irina S. Moreira
Summary: G protein-coupled receptors (GPCRs) play important roles in regulating multiple signaling pathways. Mutations in GPCR genes can significantly impact receptor structure and function. This study constructed a computational framework called MUG (Mutations Understanding GPCRs) to explore known mutations and their effects on the A17 subfamily of GPCRs. The results revealed a diverse range of mutations in A17 subfamily structures, particularly in conserved residues and domains. The mutated residues were often located at ligand binding pockets and activating microdomains, potentially disrupting receptor function. The interactive web application MUG was developed to facilitate the management and visualization of this dataset.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Article
Biology
Soumya Mitra, Amit Kumar Halder, Nilanjan Ghosh, Subhash C. Mandal, M. Natalia D. S. Cordeiro
Summary: Non-alcoholic fatty liver disease (NAFLD) is a major health hazard globally, and there are limited treatment options available. This study used cheminformatics and molecular modeling techniques to investigate the structural requirements of 3-benzamidobenzoic acid derivatives for their potency towards Farnesoid X receptor (FXR), providing important guidelines for designing novel FXR partial agonists for the management of NAFLD.
COMPUTERS IN BIOLOGY AND MEDICINE
(2023)
Review
Pharmacology & Pharmacy
Amit Kumar Halder, Soumya Mitra, Maria Natalia D. S. Cordeiro
Summary: This article reviews the recent developments in the design of multi-target drugs for the treatment of major depressive disorders. Case studies focusing on design strategies and challenges are discussed. The authors suggest exploring potential biological targets and utilizing computational modeling techniques for further research.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Catia A. Bonito, Ricardo J. Ferreira, Maria-Jose U. Ferreira, Jean-Pierre Gillet, M. Natalia D. S. Cordeiro, Daniel J. V. A. dos Santos
Summary: In this study, the impact of four P-gp mutations on drug-binding and efflux-related signal-transmission mechanism was evaluated. The repacking of the transmembrane helices induced by mutations and ligands indicates P-gp's sensitivity to perturbations in the transmembrane region. Changes in drug-binding were observed as a consequence of transmembrane helices repacking, but were not always correlated with alterations in ligand binding mode and affinity. The changes in drug efflux are mostly related to changes in drug specificity rather than effects on signal-transmission mechanism.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Multidisciplinary
Catia A. Bonito, Ricardo J. Ferreira, Maria-Jose. U. Ferreira, Fernando Duraes, Emilia Sousa, Jean-Pierre Gillet, M. Natalia D. S. Cordeiro, Daniel J. V. A. dos Santos
Summary: A medicinal chemistry study combined in silico and in vitro methodologies to identify and characterize putative allosteric drug-binding sites (aDBSs) at the interface of the transmembrane-and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified using in silico fragment-based molecular dynamics and were characterized in terms of size, polarity, and lining residues. Several compounds from a small library of thioxanthone and flavanone derivatives were found to decrease verapamil-stimulated ATPase activity, indicating allosteric efflux modulation in P-glycoprotein. Molecular docking and dynamics simulations provided insights into the binding mode of flavanone derivatives as allosteric inhibitors.
Article
Environmental Sciences
Amit Kumar Halder, Ana S. Moura, M. Natalia D. S. Cordeiro
Summary: Manufactured substances known as endocrine disrupting chemicals (EDCs) released in the environment can cause severe eco and cytotoxicity at relatively low doses. This study introduces a new multitasking quantitative structure-toxicity relationship (QSTR) modeling approach for predicting the ecotoxicity of EDCs against 170 biological species. The developed QSTR models display high accuracies, and a multitasking consensus modeling approach further improves the predictive ability.
SCIENCE OF THE TOTAL ENVIRONMENT
(2023)
Article
Multidisciplinary Sciences
Jose Guilherme de Almeida, Emma Gudgin, Martin Besser, William G. Dunn, Jonathan Cooper, Torsten Haferlach, George S. Vassiliou, Moritz Gerstung
Summary: Hematological diseases involve changes in the abundance and morphology of blood cells. Myelodysplastic syndromes (MDS) are blood cancers characterized by abnormal development of hematopoietic cells. The diagnosis of MDS requires cytomorphology analysis of bone marrow smears and complementary tests. Haemorasis, a computational method, can detect and characterize white blood cells and red blood cells in blood samples and has the potential for automated diagnosis.
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Luiz Felipe Piochi, Antonio J. Preto, Irina S. Moreira
Summary: To tackle the challenge of cancer treatment, a new drug response prediction algorithm called Drug Efficacy Leveraging Forked and Specialized networks (DELFOS) was developed. It utilizes multi-omics data from 65 cancer cell lines and structural data from over 200 compounds to predict drug sensitivity. Incorporating single-cell expression data to predict drug response was also evaluated. DELFOS was validated using datasets with unseen cell lines or drugs and compared with other state-of-the-art algorithms, achieving high prediction performance on several correlation and error metrics. Overall, DELFOS effectively leverages multi-omics data for the prediction of drug responses in thousands of drug-cell line pairs.
Article
Biochemistry & Molecular Biology
Beatriz Bueschbell, Pedro R. Magalhaes, Carlos A. V. Barreto, Rita Melo, Anke C. Schiedel, Miguel Machuqueiro, Irina S. Moreira
Summary: In this study, a computational framework was developed to generate models of GPCR dimers and identify their likely interfaces. Using the dopamine receptor D2 (D2R) homodimer as a case study, the study found that specific transmembrane domains are important at the dimer interface and provide insights into the conformational status of the receptor.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)