Article
Pharmacology & Pharmacy
Tianduanyi Wang, Otto I. Pulkkinen, Tero Aittokallio
Summary: Most drug molecules have the ability to modulate multiple target proteins, which can lead to both therapeutic effects and unwanted side effects. Evaluating the selectivity of a compound is an important factor in drug development and repurposing efforts. Traditional methods for characterizing selectivity fall short in quantifying how selective a compound is against a particular target protein. In this study, we propose an optimization-based selectivity scoring method that allows for the identification of potent and selective compounds against given kinase targets. We demonstrate the effectiveness of this method in finding highly selective compounds in computational experiments using a large-scale kinase inhibitor dataset.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Ying-Shan Ren, Hui-Lin Li, Xiu-Hong Piao, Zhi-You Yang, Shu-Mei Wang, Yue-Wei Ge
Summary: DARTS is a novel target discovery approach that is particularly adept at screening small molecule targets without requiring any structural modifications. It can reveal drug-target interactions from cells or tissues and has been applied to uncover drug-action mechanisms.
BIOCHEMICAL PHARMACOLOGY
(2021)
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
Kaiyang Liu, Xi Chen, Yue Ren, Chaoqun Liu, Tianyi Lv, Ya'nan Liu, Yanling Zhang
Summary: Polypharmacology has emerged as a new paradigm in drug discovery, playing a crucial role in addressing polygenic diseases. This paper introduces multi-target-based polypharmacology prediction (mTPP), an approach that employs virtual screening and machine learning to explore the relationship between the action of multiple targets and the overall efficacy of drugs. Through the mTPP model, potential hepatoprotective components and candidates with potential effects against drug-induced liver injury (DILI) are identified. The model demonstrates accuracy in predicting the viabilities of APAP-induced injury cells, indicating its potential for aiding the development of polypharmacology and the discovery of multi-target drugs.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Engineering, Biomedical
Yixuan Lin, Yiqi Yang, Kai Yuan, Shengbing Yang, Shuhong Zhang, Hanjun Li, Tingting Tang
Summary: This study reports a three-dimensional bioprinted osteosarcoma model that incorporates osteosarcoma cells and a mimicked extracellular matrix. Compared to traditional models, this model shows significant differences in cell cycle, metabolism, and other cellular pathways, and is more sensitive to therapies targeting the autophagy pathway.
BIOACTIVE MATERIALS
(2022)
Review
Chemistry, Medicinal
Ravinder Sharma, Gunpreet Kaur, Parveen Bansal, Viney Chawla, Vikas Gupta
Summary: Despite challenges in drug development, bioinformatics analysis using integrated genomics, proteomics, and bioinformatics can accelerate drug discovery and characterization while also predicting adverse effects and drug resistance. Combinatorial techniques such as proteomics, genomics, bioinformatics, molecular docking, and mass spectrometry have been crucial in understanding the drug-creation process. This article provides an overview of these techniques and their importance in drug development.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Peng Li, Chujie Bai, Lingmin Zhan, Haoran Zhang, Yuanyuan Zhang, Wuxia Zhang, Yingdong Wang, Jinzhong Zhao
Summary: Identifying the biological targets of a compound is crucial for understanding drug mechanisms and developing new drugs. The Connectivity Map concept connects genes, drugs, and diseases based on gene-expression signatures. However, existing methods are inefficient due to the need for reference drugs. In this study, we developed a procedure to extract target-induced gene modules and identified target gene clusters. Additionally, we proposed a gene module pair-based approach to predict novel compound-target interactions, leading to the discovery of new inhibitors for PI3K pathway proteins.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Sven Stegemann, Liz Sheehan, Alessandra Rossi, Andrew Barrett, Amrit Paudel, Abina Crean, Fabrice Ruiz, Massimo Bresciani, Fang Liu, Zakia Shariff, Margarete Shine, Christel Schmelzer, Anne-Marie Pense-Lheritier
Summary: Patient-centric drug product design is crucial in the pharmaceutical development process, and it is important to integrate patient needs and perspectives from the beginning and weigh product development decision options accordingly.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2022)
Article
Multidisciplinary Sciences
Tatphon Kongkrongtong, Ruolan Zhang, Masahiro Kawahara
Summary: The study successfully designed artificial heterodimeric receptors to activate target signaling molecules and control cell proliferation levels based on the properties of tyrosine motifs. These heterodimeric receptors may lead to a new era of tailor-made designer receptors, which could be useful for cell therapy against intractable diseases.
SCIENTIFIC REPORTS
(2021)
Article
Plant Sciences
Xiaoqian Huo, Yu Gu, Yanling Zhang
Summary: The study proposed a framework called Traditional Chinese medicine target-effect relationship spectrum (TCM-TERS) for multi-target compound screening, which provided a flexible method for drug discovery in TCM research.
JOURNAL OF ETHNOPHARMACOLOGY
(2022)
Article
Computer Science, Artificial Intelligence
Xingyu Wu, Bingbing Jiang, Yan Zhong, Huanhuan Chen
Summary: This paper investigates the discovery of multi-target Markov boundary (MB), aiming to distinguish shared MB variables and MB variables associated with single targets. Through the study of the relationship between shared MB variables and equivalent information, it is found that shared MB variables are determined by different mechanisms, which are relevant to the existence of target correlation. Based on the analysis of these mechanisms, a multi-target MB discovery algorithm is proposed to identify these two types of variables, which also achieves superiority and interpretability in feature selection tasks. Extensive experiments demonstrate the efficacy of these contributions.
IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE
(2023)
Article
Pharmacology & Pharmacy
Dandan Xia, Baoling Liu, Xiaowei Xu, Ya Ding, Qiuling Zheng
Summary: Drug target discovery is essential for drug innovation, as it elucidates the mechanism of drug action. The Fe3O4 nanoparticle-based approach developed in this study shows potential for drug-target screening in biological matrices by reducing endogenous interference and providing active sites for ligand-protein interactions.
JOURNAL OF PHARMACEUTICAL ANALYSIS
(2021)
Article
Pharmacology & Pharmacy
Ellie Esfandiari Nazzaro, Fahad Y. Sabei, Walter K. Vogel, Mohamad Nazari, Katelyn S. Nicholson, Philip R. Gafken, Olena Taratula, Oleh Taratula, Monika A. Davare, Mark Leid
Summary: Ewing's sarcoma is a rare and aggressive cancer of bone and soft tissue characterized by specific chromosomal translocations. Current cytotoxic chemotherapies effectively treat localized disease but can lead to treatment-related morbidities, and the survival rate for patients with relapsed or metastatic disease remains low. A new compound, ML111, was identified through high-throughput screening and showed promising inhibitory effects on Ewing's sarcoma cells in vitro and in vivo, suggesting its potential as a new drug lead for further preclinical studies.
Article
Computer Science, Artificial Intelligence
Meng Wu, Xiaomin Zhu, Li Ma, Weidong Bao, Zhun Fan, Yaochu Jin
Summary: Multi-robot systems outperform single robots in accomplishing challenging tasks due to their properties that single robots lack. This paper proposes a cooperative hierarchical gene regulatory network (CH-GRN) to enhance mutual cooperation between robots and utilize obstacles for more effective target entrapment. The CH-GRN includes a target-neighbour-obstacle (TNO) pattern generation method and a concentration-vector method for adaptation and obstacle avoidance. Simulation experiments and Kilobot experiments demonstrate the effectiveness of the CH-GRN in various challenging environments with different types of obstacles.
SWARM AND EVOLUTIONARY COMPUTATION
(2023)
Article
Parasitology
Philip T. LoVerde, Sevan N. Alwan, Alexander B. Taylor, Jayce Rhodes, Frederic Chevalier, Timothy JC. Anderson, Stanton F. McHardy
Summary: Human schistosomiasis is a debilitating disease affecting millions globally, with drug resistance being a major concern. Scientists have identified novel drug derivatives effective against all species of the parasite, aiming to combat resistance and improve treatment outcomes.
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
(2021)
Article
Chemistry, Medicinal
Matteo Staderini, Silvia Vanni, Arianna Colini Baldeschi, Gabriele Giachin, Marco Zattoni, Luigi Celauro, Chiara Ferracin, Edoardo Bistaffa, Fabio Moda, Daniel Perez, Ana Martinez, M. Antonia Martin, Olmo Martin-Camara, Angel Cores, Giulia Bianchini, Robert Kammerer, J. Carlos Menendez, Giuseppe Legname, Maria Laura Bolognesi
Summary: This study designed novel carbazole derivatives as pharmacological chaperones for prion diseases. These derivatives showed anti-prion activity and could detect prion protein aggregates through fluorescent staining. The compounds exhibited activity against RML-infected cell lines and have potential applications in the treatment of prion diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Giulia Panzarella, Gianmarco Gualtieri, Isabella Romeo, Stefano Alcaro
Summary: A qualified teaching method is difficult to achieve without traditional classroom lessons. However, in this innovative distance learning experiment, students have been able to change traditional teaching methods by creating a multimedia tool called MedChemBlog, which has improved their understanding of chemical structures and drug molecular mechanisms.
JOURNAL OF CHEMICAL EDUCATION
(2023)
Article
Biochemistry & Molecular Biology
Maria Dichiara, Francesca Alessandra Ambrosio, Carla Barbaraci, Rafael Gonzalez-Cano, Giosue Costa, Carmela Parenti, Agostino Marrazzo, Lorella Pasquinucci, Enrique J. Cobos, Stefano Alcaro, Emanuele Amata
Summary: The development of diazabicyclo[4.3.0]nonane and 2,7-diazaspiro[3.5]nonane derivatives as sigma receptors (SRs) ligands is discussed. The compounds were evaluated for their binding to S1R and S2R, and modeling studies were conducted to analyze the binding mode. Three notable compounds, 4b, 5b, and 8f, were further tested for their analgesic effects and functional profiles. Compound 4b showed S1R agonistic effects, while compounds 5b and 8f exhibited S1R antagonism.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Roberta Bivacqua, Isabella Romeo, Marilia Barreca, Paola Barraja, Stefano Alcaro, Alessandra Montalbano
Summary: Protein-protein interactions are an attractive target for drug design. This study focuses on the HSV-1 envelope glycoprotein D (gD) and identifies potential inhibitors for gD through protein-protein docking, dynamic simulations, and virtual screening. Four triazolo[4,5-b]pyridines are found to have good theoretical affinity towards all conformations of HSV-1 gD. This study provides a promising basis for the design of new antiviral agents targeting gD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Lais Flavia Nunes Lemes, George E. Magoulas, Andressa Souza de Oliveira, Emile Barrias, Luciana de Camargo Nascente, Renato Granado, Sara Teixeira de Macedo Silva, Nikos Assimomytis, Wanderley de Souza, Maria Laura Bolognesi, Luiz Antonio Soares Romeiro, Theodora Calogeropoulou
Summary: Synthetic ether phospholipid analogues derived from cashew nut shell liquid exhibited potent antiparasitic activity against Trypanosoma cruzi, the causative agent of Chagas disease. Two compounds (16 and 17) showed higher selectivity indices against different developmental stages of T. cruzi compared to the current drug benznidazole. This study suggests that these analogues derived from inexpensive agro-waste materials have the potential to be developed as new treatments for Chagas disease.
ACS INFECTIOUS DISEASES
(2023)
Article
Oncology
Andrea Caddeo, Marina Serra, Francesca Sedda, Andrea Bacci, Clementina Manera, Simona Rapposelli, Amedeo Columbano, Andrea Perra, Marta Anna Kowalik
Summary: The study found that TG68 has a therapeutic effect on NAFLD-associated hepatocarcinogenesis. It can significantly reduce hepatic fat accumulation, improve lipid and glucose levels, and restore the differentiation status of hepatocytes. This novel therapeutic strategy shows promise in the treatment of NAFLD-associated hepatocarcinogenesis.
FRONTIERS IN ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Gianmarco Gualtieri, Annalisa Maruca, Roberta Rocca, Fabrizio Carta, Emanuela Berrino, Alessandro Salatino, Carolina Brescia, Roberta Torcasio, Manuel Crispo, Francesco Trapasso, Stefano Alcaro, Claudiu T. Supuran, Giosue Costa
Summary: Capsaicin, a bioactive spicy molecule found in hot peppers, has been extensively studied for its beneficial effects. This study used in silico methods to evaluate its inhibitory activity against tumor-associated human CA IX and XII. In vitro assays confirmed its inhibitory activity, and a non-small cell lung cancer model showed that Capsaicin can inhibit cell migration.
Editorial Material
Biochemistry & Molecular Biology
Graeme Barker, Simona Rapposelli
Article
Chemistry, Medicinal
Serena Della Volpe, Roberta Listro, Francesca Alessandra Ambrosio, Martina Garbagnoli, Pasquale Linciano, Daniela Rossi, Giosue Costa, Stefano Alcaro, Francesca Vasile, Anna K. H. Hirsch, Simona Collina
Summary: RNA binding protein HuR plays a role in the regulation of oncogenes and tumor suppressor genes, and its dysregulation is associated with cancer. This study utilized protein-templated dynamic combinatorial chemistry to search for novel HuR ligands that can interfere with the HuR-RNA complex. Several compounds were identified and shown to effectively interfere with HuR-RNA binding, indicating their potential as anticancer agents targeting HuR-RNA interactions.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Pharmacology & Pharmacy
Jose Pena-Guerrero, Celia Fernandez-Rubio, Alfonso T. T. Garcia-Sosa, Paul A. A. Nguewa
Summary: The BRCT domain is a potential therapeutic target due to its moderately conserved folding and high sequence variations. It plays critical roles in DNA repair, recombination, and cell cycle control, and is implicated in various pathologic processes including breast, ovarian, and lung cancer. This review explores the possible roles of BRCT domains as therapeutic targets and describes their common structural features, relevant interactions and pathways, as well as their implications in pathologic processes. Additionally, it presents drugs commonly used to target these domains and offers new drug design possibilities based on their structures.
Article
Chemistry, Medicinal
Carmen Gratteri, Francesca Alessandra Ambrosio, Antonio Lupia, Federica Moraca, Bruno Catalanotti, Giosue Costa, Maria Bellocchi, Luca Carioti, Romina Salpini, Francesca Ceccherini-Silberstein, Simone La Frazia, Vincenzo Malagnino, Loredana Sarmati, Valentina Svicher, Sharon Bryant, Anna Artese, Stefano Alcaro
Summary: This study evaluated the impact of RdRp mutations on the efficacy of remdesivir in treating COVID-19. Clinical observations revealed that patients with specific mutations showed a reduced response to remdesivir, accompanied by an increase in viral load and a decrease in binding affinity to RdRp. Computational approaches helped to explain these clinical observations by analyzing the effects of mutants on the viral RNA synthesis machine and the binding patterns of remdesivir.
Article
Biochemistry & Molecular Biology
Melissa Guardigni, Letizia Pruccoli, Alan Santini, Angela De Simone, Matteo Bersani, Francesca Spyrakis, Flavia Frabetti, Elisa Uliassi, Vincenza Andrisano, Barbara Pagliarani, Paula Fernandez-Gomez, Valle Palomo, Maria Laura Bolognesi, Andrea Tarozzi, Andrea Milelli
Summary: A small set of novel GSK-3β degraders were designed and synthesized using PROTAC technology. Compound 1 emerged as the most effective PROTAC, being nontoxic to neuronal cells and able to degrade GSK-3β in a dose-dependent manner. PROTAC 1 significantly reduced neurotoxicity induced by Aβ25-35 peptide and CuSO4.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Rebecca Ferrisi, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. A. Mohamed, Giovanna Baron, Salvatore Faiella, Giulio Poli, Simona Rapposelli, Giuseppe Saccomanni, Giancarlo Aldini, Grazia Chiellini, Robert B. B. Laprairie, Clementina Manera, Gabriella Ortore
Summary: We have developed a new generation of ligands (JR compounds) that target the CB2R. These compounds combine the pharmacophoric portion of CB2R positive allosteric modulator (EC21a) with that of CB2R selective orthosteric agonist (LV62). Among the tested compounds, JR22a showed dualsteric behavior as a CB2R ligand. Computational studies confirmed the binding mode of JR22a at CB2R, and its potential to prevent neuroinflammation was investigated using a human microglial cell model.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Vladimir Curcic, Mateusz Olszewski, Natalia Maciejewska, Aleksandar Visnjevac, Tatjana Srdic-Rajic, Vladimir Dobricic, Alfonso T. Garcia-Sosa, Sanja B. Kokanov, Jovana B. Araskov, Romano Silvestri, Roland Schuele, Manfred Jung, Milan Nikolic, Nenad R. Filipovic
Summary: Heterocyclic pharmacophores such as thiazole and quinoline rings play an important role in medicinal chemistry. This study focuses on the synthesis and evaluation of a series of novel thiazolyl-hydrazones based on quinoline and hydroxyquinoline moieties. The most promising compound, 2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)-4-(4-methoxyphenyl)-1,3-thiazole (3c), shows significant anticancer activity by blocking cell-cycle progression, inducing DNA double-strand breaks, and inhibiting autophagy.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Multidisciplinary
Tereza Hofmanova, Carolina Marques, Alfonso T. Garcia-Sosa, Oscar Lopez, Luisa Leitzbach, Elisabete P. Carreiro, Aday Gonzalez-Bakker, Adrian Puerta, Holger Stark, Jose M. Padron, Jose G. Fernandez-Bolanos, Anthony J. Burke
Summary: This study focuses on the synthesis and biological activity evaluation of a series of novel N-substituted 3-aminooxindoles, revealing their selective inhibition activity against butyrylcholinesterase and their potential as drug candidates for Alzheimer's disease.
RESULTS IN CHEMISTRY
(2023)
