Review
Pharmacology & Pharmacy
Massimiliano Tognolini, Alessio Lodola, Carmine Giorgio
Summary: The recent advancement in computer power and AI algorithms has led to inexperienced scientists attempting to use computer aided drug design to discover new drugs, potentially overshadowing the importance of wet lab data and neglecting the synergy between in silico and biological data in successful drug discovery.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Chemistry, Medicinal
Lorenzo Guidetti, Riccardo Castelli, Laura Scalvini, Francesca Ferlenghi, Miriam Corrado, Carmine Giorgio, Massimiliano Tognolini, Alessio Lodola
Summary: This review summarizes the role of the Eph-ephrin system in pathological conditions and discusses the progress in developing therapeutic compounds targeting this signaling system.
Article
Chemistry, Medicinal
Maricel Gomez-Soler, Erika J. Olson, Elena Rubio de la Torre, Chunxia Zhao, Ilaria Lamberto, Dillon T. Flood, Waleed Danho, Bernhard C. Lechtenberg, Stefan J. Riedl, Elena B. Pasquale, Philip E. Dawson
Summary: The EphA4 receptor tyrosine kinase is involved in several diseases and inhibiting its activity could have therapeutic potential. Researchers have identified a peptide antagonist that specifically inhibits the binding of ephrin ligands to EphA4. They have also modified the peptide to improve its stability and activity. These derivatives could be useful for studying EphA4 in vivo and for testing EphA4 inhibition in animal models.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Iason Psilopatis, Eleni Souferi-Chronopoulou, Kleio Vrettou, Constantinos Troungos, Stamatios Theocharis
Summary: EPHs/ephrins appear to be promising treatment targets in the future for breast cancer, with EPHA2 being the most studied target.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Jesus R. Medina, Xinrong Tian, William H. Li, Dominic Suarez, James F. Mack, Louis LaFrance, Cuthbert Martyr, James Brackley, Christina Di Marco, Ralph Rivero, Dirk A. Heerding, Charles McHugh, Elisabeth Minthorn, Aishwarya Bhaskar, Jacob Rubin, Michael Butticello, Christopher Carpenter, Eldridge N. Nartey, Thomas J. Berrodin, Lorena A. Kallal, Biju Mangatt
Summary: The study identified an indirect strategy to target c-MYC and successfully discovered a series of compounds with c-MYC reducing effects. Through the medicinal chemistry program, the research team identified orally bioavailable potent c-MYC-reducing compounds. The study also developed a minimum pharmacophore model and a property-based approach to modulate pharmacokinetics properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Junhao Lin, Chunting Zeng, JiaKang Zhang, Zhenghui Song, Na Qi, Xinhui Liu, Ziyan Zhang, Aimin Li, Fengsheng Chen
Summary: EFNA4 plays a crucial role in promoting proliferation and migration of HCC cells, and its overexpression is associated with poor prognosis. EFNA4 regulates the PIK3R2/GSK3 beta/beta-catenin loop to influence the survival and migration of HCC cells.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2021)
Review
Biochemistry & Molecular Biology
Radoslaw Kaczmarek, Katarzyna Zimmer, Pawel Gajdzis, Malgorzata Gajdzis
Summary: The cornea, though simple in appearance, is a highly complex structure that requires perfect organization of cells for maintaining its biomechanical and optical properties. Eph receptors and ephrins play a crucial role in tissue organization, cell migration, and communication, particularly in the regeneration process following injuries and diseases. This review examines the current understanding of Eph and ephrins in corneal physiology and diseases, with a focus on the epithelium and endothelium, as well as their influence on corneal neovascularization.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Iason Psilopatis, Ioannis Karniadakis, Konstantinos Stylianos Danos, Kleio Vrettou, Kleita Michaelidou, Konstantinos Mavridis, Sofia Agelaki, Stamatios Theocharis
Summary: Lung cancer is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) and their ligands ephrins play a defining role in the development and progression of lung cancer. Targeting EPHs/ephrins may provide effective treatment options for precision cancer treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biology
Ronnie LaCombe, Alessandra Cecchini, Morgan Seibert, D. D. W. Cornelison
Summary: Receptor tyrosine kinases (RTKs) can function as nuclear proteins in transformed cells, and their aberrant nuclear localization is associated with cancer progression. However, the presence of nuclear RTKs in rhabdomyosarcoma (RMS) has not been reported. In this study, the researchers found that EphA1, a type of RTK, was localized in the nucleus of RMS cells. This is the first case of a nuclear RTK identified in RMS and the first time EphA1 was detected in the nucleus of any cell type.
Article
Biochemistry & Molecular Biology
Sho Kohara, Kazushige Ogawa
Summary: Kupffer cells are maintained through self-renewal within liver sinusoidal endothelial cells (LSECs). In this study, liver macrophages (Mo) were propagated from mice using mixed culture with hepatic fibroblastic cells. The propagated liver Mo expressed specific transcription factors and exhibited similar gene expression and surface markers as primary LSECs, suggesting that their properties resemble those of Kupffer cells. Further investigation revealed the expression of certain Eph receptors and ephrin ligands, as well as integrin subunits and corresponding ligands, potentially contributing to the adhesion and residence of Kupffer cells within the liver sinusoid.
Review
Pharmacology & Pharmacy
Nikhil Pillai, Aparajita Dasgupta, Sirimas Sudsakorn, Jennifer Fretland, Panteleimon D. Mavroudis
Summary: Machine learning has been widely used in the early stages of drug discovery, but its applications in pharmacokinetic/pharmacodynamic (PK/PD) field are still limited. Recent progress in ML has focused on predicting ADME properties of small molecules and PK of drug candidates, providing important insights into safety and efficacy.
DRUG DISCOVERY TODAY
(2022)
Review
Cell Biology
Lujuan Wang, Wei Li, Yong Pan
Summary: The Eph/Ephrins system plays a dual role in both suppressing and promoting tumors in primary bone tumors and bone cancer pain. Understanding the intracellular mechanisms of the Eph/Ephrins system in tumorigenesis and metastasis of bone tumors may provide a foundation for the development of targeted anti-cancer therapy.
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
Cell Biology
Michael P. Vu, Catherine Cheng
Summary: The eye lens plays a crucial role in focusing light onto the retina, while cataracts are a major cause of blindness worldwide. Recent studies have shown the importance of Eph-ephrin bidirectional signaling in maintaining lens transparency. This study investigated the expression of Eph receptors and ephrin ligands in different cell fractions of the lens, revealing the presence of multiple receptor-ligand pairs that may contribute to lens homeostasis.
Article
Pharmacology & Pharmacy
Peishan Qiu, Daojiang Li, Cong Xiao, Fei Xu, Xiaoyu Chen, Ying Chang, Lan Liu, Lei Zhang, Qiu Zhao, Yuhua Chen
Summary: The extent of gut inflammation depends on the gut barrier's integrity and enteric neuroimmune interactions. The role of Eph/ephrin signaling in regulating gut homeostasis, inflammation, neuroimmune interactions, and pain pathways is critical. Targeting the Eph/ephrin system provides innovative treatments for gut inflammation disorders.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Katsuaki Ieguchi, Takeshi Tomita, Toshifumi Takao, Tsutomu Omori, Taishi Mishima, Isao Shimizu, Massimiliano Tognolini, Alessio Lodola, Takuya Tsunoda, Shinichi Kobayashi, Satoshi Wada, Yoshiro Maru
Summary: The study revealed that tumor-derived ephrin-A1 plays a significant role in a worse prognosis, with ADAM-mediated cleavage of ephrin-A1 being a key factor in lung metastasis. Inhibition of cleavage or antagonization of receptors can greatly reduce lung metastasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biotechnology & Applied Microbiology
Marco Rusnati, Giulia Paiardi, Chiara Tobia, Chiara Urbinati, Alessio Lodola, Pasqualina D'Ursi, Miriam Corrado, Riccardo Castelli, Rebecca C. Wade, Massimiliano Tognolini, Paola Chiodelli
Summary: UniPR1331, a derivative of 3 beta-hydroxy-Delta(5)-cholenic acid, has been shown to inhibit Eph-ephrin interaction and VEGFR2 activation, leading to the suppression of tumor cell-driven angiogenesis. These findings highlight the potential of Delta(5)-cholenic acid as a promising molecular scaffold for the development of multitarget antiangiogenic compounds.
CANCER GENE THERAPY
(2022)
Correction
Biotechnology & Applied Microbiology
Marco Rusnati, Giulia Paiardi, Chiara Tobia, Chiara Urbinati, Alessio Lodola, Pasqualina D'Ursi, Miriam Corrado, Riccardo Castelli, Rebecca C. Wade, Massimiliano Tognolini, Paola Chiodelli
CANCER GENE THERAPY
(2022)
Article
Chemistry, Medicinal
Gian Marco Elisi, Laura Scalvini, Alessio Lodola, Marco Mor, Silvia Rivara
Summary: The study investigated the feasibility of 2-iodomelatonin entering MT1 and MT2 receptors through a lateral channel and revealed different unbinding trajectories for the ligand in those receptors. The results suggest that the side-chain flexibility of Tyr5.38 plays a role in the egress of 2-iodomelatonin and may affect receptor subtype selectivity.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Physical
Sergio Marti, Kemel Arafet, Alessio Lodola, Adrian J. Mulholland, Katarzyna Swiderek, Vicent Moliner
Summary: A simulation study explored the inhibition mechanism of the SARS-CoV-2 main protease, revealing a two-step process strongly influenced by the functional groups in the inhibitors' warheads. The results and methods used in the study can guide the design of efficient inhibitors for the SARS-CoV-2 main protease.
Article
Chemistry, Medicinal
Francesca Ferlenghi, Carmine Giorgio, Matteo Incerti, Lorenzo Guidetti, Paola Chiodelli, Marco Rusnati, Massimiliano Tognolini, Federica Vacondio, Marco Mor, Alessio Lodola
Summary: This study improved the oral bioavailability of UniPR129 by functionalizing the 3α-hydroxyl group on the LCA steroidal ring to 3-hydroxyimine, and successfully synthesized the 3-hydroxyimine derivative UniPR500. UniPR500 demonstrated higher stability and improved pharmacological profile, serving as an EphA2 receptor antagonist.
Review
Chemistry, Medicinal
Lorenzo Guidetti, Riccardo Castelli, Laura Scalvini, Francesca Ferlenghi, Miriam Corrado, Carmine Giorgio, Massimiliano Tognolini, Alessio Lodola
Summary: This review summarizes the role of the Eph-ephrin system in pathological conditions and discusses the progress in developing therapeutic compounds targeting this signaling system.
Review
Pharmacology & Pharmacy
Gian Marco Elisi, Laura Scalvini, Alessio Lodola, Annalida Bedini, Gilberto Spadoni, Silvia Rivara
Summary: This review describes the design strategies used in the discovery of melatonin receptor ligands, guided by in silico approaches and molecular modeling techniques. Different types of ligands with various activity profiles have been developed, including agonist/antagonist and subtype-selective compounds. In silico drug discovery has played a crucial role in the design of novel ligands targeting melatonin receptors, providing insights into pharmacological characterization and therapeutic perspectives.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Chemistry, Medicinal
Francesca Galvani, Laura Scalvini, Silvia Rivara, Alessio Lodola, Marco Mor
Summary: The mechanism of action of three different types of monoglyceride lipase (MGL) inhibitors on the enzyme was investigated, and it was found that the expulsion of the leaving group has a significant impact on MGL carbamoylation. Simulation results showed that changes in the electronic structure of the leaving group affect reaction energetics, and different types of inhibitors follow different carbamoylation pathways. These findings contribute to understanding structure-activity relationships and provide insights for the design of covalent inhibitors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Alessandro Papa, Silvia Pasquini, Francesca Galvani, Mariarosaria Cammarota, Chiara Contri, Gabriele Carullo, Sandra Gemma, Anna Ramunno, Stefania Lamponi, Beatrice Gorelli, Simona Saponara, Katia Varani, Marco Mor, Giuseppe Campiani, Francesca Boscia, Fabrizio Vincenzi, Alessio Lodola, Stefania Butini
Summary: The neuroprotective performance of the endocannabinoid system (ECS) against neuroinflammation can be significantly enhanced by inhibiting the key ECS enzyme FAAH. In this study, a series of carbamate-based FAAH inhibitors were developed with improved drug properties compared to previous analogues. These inhibitors showed nanomolar potency, good water solubility, and chemical stability. They exhibited excellent selectivity against monoacylglycerol lipase and cannabinoid receptors, and demonstrated reversible mechanisms of action without toxicity or cardiac effects. Selected analogues displayed notable neuroprotective effects against oxidative stress and neuroinflammation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Francesca Romana Ferrari, Carmine Giorgio, Alfonso Zappia, Vigilio Ballabeni, Simona Bertoni, Elisabetta Barocelli, Laura Scalvini, Francesca Galvani, Marco Mor, Alessio Lodola, Massimiliano Tognolini
Summary: It has been demonstrated that the Eph-ephrin system, particularly the EphA2 receptor, plays a key role in supporting tumor growth, invasion, metastasis, and neovascularization. In this study, new commercially available FXR agonists, including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl, and Vonafexor, were characterized as potential Eph ligands. Molecular modeling investigations and binding assays showed that Cilofexor specifically and reversibly binds to the EphA2 receptor with a ki value in the low micromolar range.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Kemel Arafet, Laura Scalvini, Francesca Galvani, Sergio Marti, Vicent Moliner, Marco Mor, Alessio Lodola
Summary: Targeted covalent inhibitors show potential for drug discovery, specifically for kinases. Targeting the catalytic lysine of EGFR has gained attention for overcoming resistance caused by the C797S mutation. Sulfonyl fluoride derivatives have been reported as inhibitors of EGFRL858R/T790M/C797S through sulfonylation of Lys745. However, the mechanism behind this process is poorly understood.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Francesca Galvani, Daniele Pala, Alberto Cuzzolin, Laura Scalvini, Alessio Lodola, Marco Mor, Andrea Rizzi
Summary: In this study, two metadynamics protocols were used to estimate the residence times of muscarinic M3 receptor antagonists. The results showed that both computational methods were able to accurately rank compounds according to their experimental residence times.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Claudio Festuccia, Miriam Corrado, Alessandra Rossetti, Riccardo Castelli, Alessio Lodola, Giovanni Luca Gravina, Massimiliano Tognolini, Carmine Giorgio
Summary: This study demonstrated the inhibitory effects of Eph antagonism on prostate cancer both in vitro and in vivo. The Eph antagonist UniPR1331 inhibited PC3 cell growth, induced apoptosis, and downregulated epithelial mesenchymal transition markers. Furthermore, UniPR1331 reduced PC3 cell migration, invasion, and vasculomimicry capabilities.
Article
Chemistry, Physical
Sergio Marti, Kemel Arafet, Alessio Lodola, Adrian J. Mulholland, Katarzyna Swiderek, Vicent Moliner
Summary: This study simulated the inhibition mechanism of the main protease of the novel coronavirus, revealing a two-step mechanism for two proposed peptidyl covalent inhibitors.
