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)
Review
Pharmacology & Pharmacy
Silvia Pasquini, Chiara Contri, Martina Cappello, Pier Andrea Borea, Katia Varani, Fabrizio Vincenzi
Summary: Adenosine receptors (ARs) have great therapeutic potential for a wide range of pathological conditions. Targeting allosteric sites with allosteric modulators can overcome the limitations of orthosteric ligands. Promising results have been achieved with various allosteric modulators, but more research is needed for certain AR subtypes.
FRONTIERS IN PHARMACOLOGY
(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
Multidisciplinary Sciences
Gemma Turon, Jason Hlozek, John G. Woodland, Ankur Kumar, Kelly Chibale, Miquel Duran-Frigola
Summary: Streamlined data-driven drug discovery remains challenging, especially in resource-limited settings. Here, the authors present ZairaChem, an AI/ML tool that streamlines QSAR/QSPR modelling, implemented for the first time at the H3D Centre in South Africa.
NATURE COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Regis Guieu, Clara Degioanni, Julien Fromonot, Lucille De Maria, Jean Ruf, Jean Claude Deharo, Michele Brignole
Summary: Adenosine plays a role in neuro-humoral syncope through its interaction with different receptor subtypes. The modulation of ion channels, calcium channels, and cAMP production are involved in adenosine's effects on the cardiovascular system. Adenosine receptor antagonists may be useful in the treatment of syncope.
Article
Chemistry, Medicinal
Tuomo Kalliokoski, Henna Kettunen, Esa Kumpulainen, Emilia Kettunen, Gabriel Thieulin-Pardo, Lars Neumann, Maren Thomsen, Ralf Paul, Alina Malyutina, Maria Georgiadou
Summary: This study conducted a structure-based virtual screening on commercially available chemical space, leading to the discovery of two novel MAT2A-inhibitor chemical series. X-ray crystallography confirmed the binding modes of the compounds. Both series exhibited nanomolar activity in the biochemical MAT2A inhibition assay and single-digit micromolar activity in the proliferation assay. These findings and the related structural data could be valuable for drug discovery projects related to MAT2A.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Na Lv, Qinxiang Kong, Hui Zhang, Jiabin Li
Summary: In this study, a hybrid virtual screening strategy was employed to discover new inhibitors of PBP2a, a key protein in MRSA resistance. Three compounds (Hit 2, Hit 3, and Hit 10) showed excellent anti-MRSA activity and low toxicity in vitro, with Hit 2 exhibiting the best binding affinity to PBP2a. Surface plasmon resonance experiments and molecular dynamics simulations confirmed the affinity of these compounds to PBP2a, suggesting their potential as non-β-lactam antibiotics against MRSA.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Monika Kubacka, Szczepan Mogilski, Marek Bednarski, Krzysztof Pociecha, Artur Swierczek, Noemi Nicosia, Jakub Schabikowski, Michal Zaluski, Grazyna Chlon-Rzepa, Joerg Hockemeyer, Christa E. Mueller, Katarzyna Kiec-Kononowicz, Magdalena Kotanska
Summary: The platelet aggregation inhibitory activity of selected xanthine-based adenosine A(2A) and A(2B) receptor antagonists was investigated, and the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). The highest inhibitory activity against PDE3A was observed in TB-42, along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of the compounds may be due to inhibition of PDEs, leading to increased cAMP and/or cGMP concentrations in platelets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Elissa A. Fink, Jun Xu, Harald Huebner, Joaom. Braz, Philipp Seemann, Charlotte Avet, Veronica Craik, Dorothee Weikert, Maximilian F. Schmidt, Chase M. Webb, Nataliya A. Tolmachova, Yurii S. Moroz, Xi-Ping Huang, Chakrapani Kalyanaraman, Stefan Gahbauer, Geng Chen, Zheng Liu, Matthew P. Jacobson, John J. Irwin, Michel Bouvier, Yang Du, Brian K. Shoichet, Allan I. Basbaum, Peter Gmeiner
Summary: A new class of α(2A)AR agonists has been discovered through computational docking and experimental validation, which exhibit on-target analgesic activity in multiple pain models without inducing sedation.
Article
Multidisciplinary Sciences
Antonio N. Mauro, Paul J. Turgeon, Sahil Gupta, Koroboshka Brand-Arzamendi, Hao Chen, Jeanie H. Malone, Robin Ng, Kevin Ho, Michelle Dubinsky, Caterina Di Ciano-Oliveira, Christopher Spring, Pamela Plant, Howard Leong-Poi, John C. Marshall, Philip A. Marsden, Kim A. Connelly, Krishna K. Singh
Summary: Angiogenesis is critical for tumor progression. Blocking VEGF signaling to inhibit angiogenesis can halt tumor progression, but resistance often occurs. This study screened for novel angiogenesis inhibitors using zebrafish and human umbilical vein endothelial cells (HUVECs), and identified PD 81,723 as a potential inhibitor. PD 81,723 showed anti-angiogenic effects in zebrafish and HUVECs, without inducing apoptosis but downregulating several important proteins involved in angiogenesis.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Naiem T. Issa, Stephen W. Byers, Sivanesan Dakshanamurthy
Summary: ES-Screen is a novel electrostatics-driven virtual screening method that optimizes electrostatic and nonpolar interactions by replacing electrostatic interaction energies, providing a unique approach for finding biologically relevant ligand-protein interactions in drug discovery.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Andrej Emanuel Cotman, Martina Durcik, Davide Benedetto Tiz, Federica Fulgheri, Daniela Secci, Masa Sterle, Stefan Mozina, Ziga Skok, Nace Zidar, Anamarija Zega, Janez Ilas, Lucija Peterlin Masic, Tihomir Tomasic, Diarmaid Hughes, Douglas L. Huseby, Sha Cao, Linnea Garoff, Talia Berruga Fernandez, Paraskevi Giachou, Lisa Crone, Ivailo Simoff, Richard Svensson, Bryndis Birnir, Sergiy V. Korol, Zhe Jin, Francisca Vicente, Maria C. Ramos, Mercedes de la Cruz, Bjorn Glinghammar, Lena Lenhammar, Sara R. Henderson, Julia E. A. Mundy, Anthony Maxwell, Clare E. M. Stevenson, David M. Lawson, Guido V. Janssen, Geert Jan Sterk, Danijel Kikelj
Summary: We have developed compounds that show promising activity against antibiotic-resistant bacteria, Acinetobacter baumannii and Pseudomonas aeruginosa, which are on the WHO priority list. Compound 27, derived from DNA gyrase inhibitor 1, exhibited improved solubility, inhibition of topoisomerase IV, and no cross-resistance to novobiocin. Further optimization steps led to analogs of 27 with improved plasma distribution and retained anti-Gram-negative activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Jorge Barbazan, Maria Majellaro, Anton L. Martinez, Jose M. Brea, Eddy Sotelo, Miguel Abal
Summary: This study explored the gene expression of G-protein coupled receptors (GPCRs) in colorectal cancer cells and stromal cells. The adenosine receptor 2B (A(2B)AR) was identified as a specific target in cancer cells and fluorescent ligands were used for target visualization and validation. The fluorescent ligands showed effective labeling of A(2B)AR in living cells and complex 3D cellular systems, and selective antagonists of A(2B)AR were found to reduce tumor cell proliferation. This study suggests the use of fluorescent ligands for GPCR characterization and target validation in cancer drug screening.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Chemistry, Multidisciplinary
Morgane Mannes, Charlotte Martin, Sarah Triest, Marilisa Pia Dimmito, Adriano Mollica, Toon Laeremans, Christel J. Menet, Steven Ballet
Summary: GPCRs are important membrane proteins in modern medicine. Peptidomimetics described in this study can mimic G proteins in stabilizing the active state of receptors, facilitating the discovery of agonist drugs.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Laura Gallego-Yerga, Rodrigo Ochoa, Isaias Lans, Carlos Pena-Varas, Melissa Alegria-Arcos, Pilar Cossio, David Ramirez, Rafael Pelaez
Summary: Tubulin is a validated target for various drugs, but there is a lack of anticancer drugs targeting the colchicine site. By utilizing X-ray structures of tubulin in complex with ligands, researchers designed a novel tubulin modulator by combining scaffolds that best fit the ensemble pharmacophore-representation.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Ethics
Karoline Boegle, Marta Bassi, Angela Comanducci, Katja Kuehlmeyer, Philipp Oehl, Theresa Raiser, Martin Rosenfelder, Jaco Diego Sitt, Chiara Valota, Lina Willacker, Andreas Bender, Eva Grill
Summary: Family caregivers of patients with disorders of consciousness emotionally engage in conversations based on the value of the information provided, seeking positive information, comfort, and empathy, and requiring detailed information to gain a deep understanding and clear picture of their loved one's condition.
Article
Medicine, Legal
Peter S. R. Wright, Graham F. Smith, Katharine A. Briggs, Robert Thomas, Gareth Maglennon, Paulius Mikulskis, Melissa Chapman, Nigel Greene, Benjamin U. Phillips, Andreas Bender
Summary: Virtual Control Groups (VCGs) based on Historical Control Data (HCD) have the potential to reduce animal usage in preclinical toxicity testing. Replacing Concurrent Control Groups (CCGs) with VCGs can improve the consistency of study outcomes. However, some covariates may affect the identification of treatment-relatedness.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Medicine, Legal
Peter S. R. Wright, Katharine A. Briggs, Robert Thomas, Graham F. Smith, Gareth Maglennon, Paulius Mikulskis, Melissa Chapman, Nigel Greene, Benjamin U. Phillips, Andreas Bender
Summary: By comparing histopathological findings and target organ toxicities across different preclinical species, this study found that positive concordance is more common than negative concordance in histopathological results, and there is low concordance in target organ toxicities. It provides new statistically significant associations between preclinical species but finds that concordance is rare.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Hongbin Yang, Olga Obrezanova, Amy Pointon, Will Stebbeds, Jo Francis, Kylie A. Beattie, Peter Clements, James S. Harvey, Graham F. Smith, Andreas Bender
Summary: Functional changes to cardiomyocytes during drug discovery pose risks of cardiovascular adverse effects. A new approach using calcium transients in hiPSC-CMs has been developed to detect early contractility changes. By deriving 25 parameters from each calcium transient waveform, a modified Random Forest method was able to predict inotropic effects with improved accuracy compared to traditional methods. This study demonstrates the potential of advanced waveform parameters and machine learning techniques in predicting cardiovascular risks associated with inotropic effects.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yingli Zhu, Hongbin Yang, Liwen Han, Lewis H. Mervin, Layla Hosseini-Gerami, Peihai Li, Peter Wright, Maria-Anna Trapotsi, Kechun Liu, Tai-Ping Fan, Andreas Bender
Summary: Uncontrolled angiogenesis is a common problem in many deadly and debilitating diseases, and traditional Chinese medicine offers an alternative source for developing drugs to regulate angiogenesis. In this study, 100 traditional Chinese medicine-derived metabolites were investigated, and 51 metabolites were found to have angiogenic activity. The mechanisms of action of these metabolites were analyzed, and a decision tree was generated to predict their poly-pharmacology. In vitro and in vivo experiments were conducted to validate the predictions and identify specific metabolites with pro-angiogenic or anti-angiogenic effects.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Biochemical Research Methods
Anika Liu, Srijit Seal, Hongbin Yang, Andreas Bender
Summary: This review discusses various sources of information, including biological data such as gene expression and cell morphology, for better understanding and predicting compound activity and safety-related endpoints. It introduces different types of chemical, in vitro, and in vivo information that can describe compounds and adverse effects. The review explores how compound descriptors based on chemical structure or biological perturbation response can predict safety-related endpoints, and how biological data can enhance understanding of adverse effects mechanistically. These applications highlight the potential of large-scale biological information in predictive toxicology and drug discovery projects.
Article
Biochemical Research Methods
Layla Hosseini-Gerami, Ixavier Alonzo Higgins, David A. Collier, Emma Laing, David Evans, Howard Broughton, Andreas Bender
Summary: This study performed a comprehensive evaluation of four causal reasoning algorithms in different networks, and found that the choice of algorithm and network greatly influenced the performance of causal reasoning algorithms. SigNet performed best in recovering direct targets, while CARNIVAL with Omnipath network excelled in recovering informative signaling pathways. The performance of causal reasoning methods was somewhat correlated with the connectivity and biological role of the targets.
BMC BIOINFORMATICS
(2023)
Article
Biochemistry & Molecular Biology
Benoit Baillif, Jason Cole, Patrick McCabe, Andreas Bender
Summary: Deep generative models have become popular in chemical design. This article focuses on explicit 3D molecular generative models, which have gained interest recently. Multiple models have been developed to generate molecules in 3D, providing atom types and coordinates. These models can be guided by structural information and produce molecules with similar docking scores to known actives, but they are less efficient and sometimes generate unrealistic conformations. The article advocates for a unified benchmark of metrics and proposes future perspectives to be addressed.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(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
Medicine, Research & Experimental
Koichi Handa, Peter Wright, Saki Yoshimura, Michiharu Kageyama, Takeshi Iijima, Andreas Bender
Summary: This study developed machine learning models to predict plasma concentration-time profiles of drugs after intravenous and oral administration. The predictive accuracy of different models was investigated, and random forest showed the best performance. The importance of in vitro pharmacokinetic parameters was also explored and found to be well-reflected in the model.
MOLECULAR PHARMACEUTICS
(2023)
Article
Chemistry, Medicinal
Lavinia-Lorena Pruteanu, Andreas Bender
Summary: Gene expression and cell morphology data are important for drug discovery. They can describe different biological states and the effects of compound treatment, and are useful for drug repurposing and compound characterization. This paper discusses recent advances in this area, and emphasizes the need for better understanding the applicability domain of readouts and their relevance for decision-making.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Srijit Seal, Hongbin Yang, Maria-Anna Trapotsi, Satvik Singh, Jordi Carreras-Puigvert, Ola Spjuth, Andreas Bender
Summary: In this study, similarity-based merger models were developed to combine outputs of individual models trained on cell morphology and chemical structure, as well as the structural and morphological similarities of compounds in the test dataset. Logistic regression models were used to apply these similarity-based merger models on predictions and similarities from 177 assays, achieving better performance compared to using structural or cell painting models alone. These results demonstrate that similarity-based merger models combining structure and cell morphology can accurately predict a wide range of biological assay outcomes and expand the applicability domain.
JOURNAL OF CHEMINFORMATICS
(2023)
Article
Chemistry, Medicinal
Lavinia-Lorena Pruteanu, Andreas Bender
Summary: Gene expression and cell morphology data are valuable in drug discovery, providing insight into biological systems in different states and after compound treatment. This article discusses recent advances in using these data for drug repurposing and highlights the need for further understanding of the applicability domain and relevance of the readouts for decision making.
ACS MEDICINAL CHEMISTRY LETTERS
(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
Maria-Anna Trapotsi, Elizabeth Mouchet, Guy Williams, Tiziana Monteverde, Karolina Juhani, Riku Turkki, Filip Miljkovic, Anton Martinsson, Lewis Mervin, Kenneth R. Pryde, Erik Mullers, Ian Barrett, Ola Engkvist, Andreas Bender, Kevin Moreau
Summary: This study used unbiased high-content imaging method Cell Painting to identify phenotypic signatures of PROTACs and discovered mitochondrial toxicity signatures that could not be expected by screening individual PROTAC components. The results highlight the potential of unbiased phenotypic methods in identifying toxic signatures and impacting drug design.
ACS CHEMICAL BIOLOGY
(2022)