Article
Biochemistry & Molecular Biology
Amit Kumar Halder, M. Natalia D. S. Cordeiro
Summary: In this study, multi-target Quantitative Structure-Activity Relationship (mt-QSAR) models were systematically evaluated to probe the inhibitory activity of AKT, with the best predictive models identified using different feature selection algorithms and machine learning tools. The models were validated internally and externally, and used to screen a kinase inhibitor library for potential pan-AKT inhibitors. Molecular dynamics simulations were then employed to estimate the binding affinity of the selected inhibitors towards the three isoforms of AKT, providing important guidelines for the discovery of novel AKT inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Sunday N. Okafor, Pavimol Angsantikul, Hashim Ahmed
Summary: This research utilized computational tools to screen a large compound library and identified potential HIV-1 protease inhibitors. Two optimized molecules showed promising activity and should be further investigated in vitro and in clinical trials.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
XiaoYang Li, HuanXian Wu, Kai-Wen Feng, JiaHuan Xu, Shaoyu Wu, Zhong-Zhen Zhou, Xiao-Fang Li
Summary: In this study, nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these analogues, 3,5-dimethoxyphenylpyridines 8j with a 4-methoxybenzyl aniline side-chain and trimethoxyphenylpyridine 8o with a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against glioma, colon carcinoma, and lung cancer. These compounds exhibited lower cytotoxicity towards normal cells and higher antiproliferative activities against specific cancer cell lines. Further investigations revealed that 8o exhibited higher tubulin polymerization inhibitory activity and induced cell cycle arrest and cellular apoptosis by disrupting the microtubule network.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Vibhu Jha, Marzia Biagi, Valeria Spinelli, Miriana Di Stefano, Marco Macchia, Filippo Minutolo, Carlotta Granchi, Giulio Poli, Tiziano Tuccinardi
Summary: Monoacylglycerol lipase (MAGL) is an important enzyme in the endocannabinoid system, associated with various pathological conditions, making it a promising drug design target. A study developed a virtual screening protocol combined with molecular docking and dynamics simulations to identify two promising reversible MAGL inhibitors, VS1 and VS2.
Article
Biochemistry & Molecular Biology
Arooma Maryam, Abdul Rauf Siddiqi, Sundeep Chaitanya Vedithi, Abdulilah Ece, Rana Rehan Khalid
Summary: Through e-pharmacophore based screening and molecular dynamics simulation, we have discovered compounds that selectively inhibit PDE5A compared to PDE6A. These compounds stably bind to PDE5A and show weaker binding to PDE6A. After optimization and therapeutic interventions, this compound may become a promising PDE5A selective inhibitor.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Tao Pan, Yanrong Dan, Dafeng Guo, Junhao Jiang, Dongzhi Ran, Lin Zhang, Binghua Tian, Jianyong Yuan, Yu Yu, Zongjie Gan
Summary: The newly designed compound 10f showed potent inhibitory activity against both ALK and HDAC, effective against resistant mutants and exhibiting significant anti-proliferative effects on cancer cells at low concentrations.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Sergio Celis, Fruzsina Hobor, Thomas James, Gail J. Bartlett, Amaurys A. Ibarra, Deborah K. Shoemark, Zsofia Hegedus, Kristina Hetherington, Derek N. Woolfson, Richard B. Sessions, Thomas A. Edwards, David M. Andrews, Adam Nelson, Andrew J. Wilson
Summary: The study presents a general approach to discover orthosteric PPI inhibitors that mimic specific secondary protein structures, validated through experimental examples. Low μM activity selective PPI inhibitors were discovered for two unrelated PPIs, with defined structure-activity relationships established through hit expansion. The approach is believed to have the potential to enable the discovery of inhibitors for a wide range of unrelated secondary structure-mediated PPIs.
Article
Biochemistry & Molecular Biology
Mebarka Ouassaf, Ossama Daoui, Sarfaraz Alam, Souad Elkhattabi, Salah Belaidi, Samir Chtita
Summary: In this study, a computer-aided methodology combining molecular docking and pharmacophore screening was used to identify potent inhibitors against FLT3. Structure-based pharmacophore characteristics resistant to FLT3 inhibitors were identified, and two hits with potential inhibitory activity were found.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Medicinal
Vajja Krishna Rao, Anvesh Ashtam, Dulal Panda, Sankar K. Guchhait
Summary: This study investigated the discovery of new tubulin polymerization inhibitors using a natural product-inspired strategy and incorporation of an NP-privileged motif. The synthesized compounds showed significant antiproliferative effects in breast cancer cells, and one compound demonstrated potent inhibitory activity on tubulin polymerization and induction of cell death.
Article
Chemistry, Physical
Qiushuang Gao, Peng Yao, Ying Wang, Qizheng Yao, Ji Zhang
Summary: In this study, in silico simulations and drug repurposing approaches were used to identify promising HDAC2 inhibitors. Compounds DB08464, DB00731, DB13930, and DB13696 showed stable binding to HDAC2 and favorable interactions. Additionally, one of the screened compounds, the antiviral drug DB13696, exhibited significant anti-proliferative activity on HepG2 cells with high HDAC2 expression.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Biochemistry & Molecular Biology
Qi-Xuan Xu, Liang Guo, Yuan Li, Zhao-Wei Wang, Po Hu, Guang-Ming Yang, Yang Pan
Summary: Rho-associated kinase-1 (ROCK1) has emerged as a promising therapeutic target in various diseases and benzamide has been widely studied as a ROCK1 inhibitor. In this study, a series of ROCK1 inhibitors derived from N-methyl-4-(4-pyrazolidinyl) benzamides (MPBs) were investigated using multiple computational methods, leading to the identification of potential inhibitors with superior predicted activities and stability in the binding pocket. These findings provide valuable insights for the rational design and development of novel ROCK1 inhibitors.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Mladen Koravovic, Anand Mayasundari, Gordana Tasic, Fatemeh Keramatnia, Timothy R. Stachowski, Huarui Cui, Sergio C. Chai, Barbara Jonchere, Lei Yang, Yong Li, Xiang Fu, Ryan Hiltenbrand, Leena Paul, Vibhor Mishra, Jeffery M. Klco, Martine F. Roussel, William CK. Pomerantz, Marcus Fischer, Zoran Rankovic, Vladimir Savic
Summary: An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired the synthesis of JQ1 derived heterocyclic amides. These compounds displayed improved profiles compared to JQ1 and birabresib as potent BET inhibitors. A specific compound 1q (SJ1461) showed excellent affinity to both BRD4 and BRD2 and high potency in acute leukaemia and medulloblastoma cell lines. The co-crystal structure of 1q with BRD4-BD1 revealed polar interactions, explaining the observed affinity improvements. Furthermore, pharmacokinetic studies suggested that the heterocyclic amide moiety improved drug-like features. Our study led to the discovery of the potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biology
Lili Jiang, Zhongmin Zhang, Zhen Wang, Yong Liu
Summary: This study identified two potential KIT inhibitors through pharmacophore modeling and molecular docking, with good ADMET properties. Docking simulations showed strong hydrogen bond interactions between the compounds and different KIT mutant proteins. These compounds have the potential for further development as KIT inhibitors for GIST treatment.
OPEN LIFE SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Geetha Durairaj, Ozlem Demir, Bryant Lim, Robert Baronio, Delia Tifrea, Linda V. Hall, Jacob C. DeForest, Linda Lauinger, Maryam M. Jebril Fallatah, Clinton Yu, Hosung Bae, Da-Wei Lin, Jin Kwang Kim, Faezeh Salehi, Cholsoon Jang, Feng Qiao, Richard H. Lathrop, Lan Huang, Robert Edwards, Scott Rychnovsky, Rommie E. Amaro, Peter Kaiser
Summary: This study utilized a virtual screening approach to identify small molecules that can reactivate the tumor suppressor p53. The UCI-LC0023 compound series was explored in depth and shown to restore the function of mutant p53, prevent tumor progression in cells carrying mutant p53, and induce transcription programs dependent on p53 activity.
CELL CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Feng-Lung Tsai, Han-Li Huang, Mei-Jung Lai, Jing-Ping Liou, Shiow-Lin Pan, Chia-Ron Yang
Summary: The study found that MPT0G236, a pan-HDAC inhibitor, specifically targets malignant tumor cells and exhibits significant anticancer activity in human colorectal cancer cells, making it a potential candidate for colorectal cancer treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Hematology
Cristina Fugazza, Gloria Barbarani, Sudharshan Elangovan, Maria Giuseppina Marini, Serena Giolitto, Isaura Font-Monclus, Maria Franca Marongiu, Laura Manunza, John Strouboulis, Claudio Cantu, Fabio Gasparri, Silvia M. L. Barabino, Yukio Nakamura, Sergio Ottolenghi, Paolo Moi, Antonella Ellena Ronchi
Summary: Coup-TFII is identified as a specific activator of the gamma-globin gene, playing a role in activating gamma-globin expression during early embryonic/fetal stages. Overexpression of Coup-TFII can overcome the repression of gamma-globin in adult cells, while knockout of Coup-TFII increases the beta/gamma+beta globin ratio.
Article
Oncology
Meera Saxena, Ravi K. R. Kalathur, Natalia Rubinstein, Andrea Vettiger, Nami Sugiyama, Melanie Neutzner, Mairene Coto-Llerena, Venkatesh Kancherla, Caner Ercan, Salvatore Piscuoglio, Jonas Fischer, Ernesta Fagiani, Claudio Cantu, Konrad Basler, Gerhard Christofori
Article
Biochemistry & Molecular Biology
Vida Vafaizadeh, David Buechel, Natalia Rubinstein, Ravi K. R. Kalathur, Lorenzo Bazzani, Meera Saxena, Tomas Valenta, George Hausmann, Claudio Cantu, Konrad Basler, Gerhard Christofori
Summary: Canonical Wnt/β-catenin signaling plays a significant role in tumor initiation, progression, and metastasis in various cancer types. However, the binding of beta-catenin to Bcl9/Bcl9L is found to modulate rather than critically required for breast cancer growth and malignant progression. Interfering with the interaction between these proteins can reduce tumor growth and metastasis.
Article
Chemistry, Inorganic & Nuclear
Saonli Roy, Loganathan Rangasamy, Assia Nouar, Christiane Koenig, Vanessa Pierroz, Simon Kaeppeli, Stefano Ferrari, Malay Patra, Gilles Gasser
Summary: This study developed organometallic-containing peptides as inhibitors of CDC25 phosphatases, with the ruthenocene derivative showing the highest potency. Despite unsuccessful cellular studies, the observed enzyme inhibition validates this approach and sets the stage for future research in this direction.
Article
Multidisciplinary Sciences
David Buechel, Nami Sugiyama, Natalia Rubinstein, Meera Saxena, Ravi K. R. Kalathur, Fabiana Luond, Vida Vafaizadeh, Tomas Valenta, George Hausmann, Claudio Cantu, Konrad Basler, Gerhard Christofori
Summary: The transcriptional activity of beta-catenin plays a crucial role in the malignant progression of breast cancer, affecting tumor growth, invasion, and metastasis formation. This contrasts its adhesion function, highlighting the importance of Wnt/beta-catenin-dependent transcription in cancer progression.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Miriam Pagin, Mattias Pernebrink, Mattia Pitasi, Federica Malighetti, Chew-Yee Ngan, Sergio Ottolenghi, Giulio Pavesi, Claudio Cantu, Silvia K. Nicolis
Summary: The transcription factor SOX2 is crucial for brain development and neural stem cell maintenance. Study shows that FOS, a SOX2 transcriptional target, can rescue defects in neuronal production caused by Sox2 deletion.
Article
Pharmacology & Pharmacy
Luca Fasolato, Massimiliano Magro, Giorgio Cozza, Ferruccio Sbarra, Simone Molinari, Enrico Novelli, Fabio Vianello, Andrea Venerando
Summary: The study introduced a self-assembled core-shell nanohybrid (SAMN@EGCG) that successfully delivered EGCG into cancer cells with an impressive protein kinase CK2 inhibition effect. Additionally, the nanohybrid displayed improved antimicrobial effects against Gram-negative bacterium Pseudomonas aeruginosa.
Article
Biochemistry & Molecular Biology
Lorenzo Badenetti, Rosa Manzoli, Michela Rubin, Giorgio Cozza, Enrico Moro
Summary: Among cytoprotective mechanisms, eukaryotic cells rely on the Nrf2 transcription factor to initiate a complex transcriptional program during biological stressors, including oxidative stress. Nrf2 has recently been found to play a crucial role in various research fields, such as cancer, inflammatory disorders, and age-related neurological diseases. In this study, a novel Nrf2/ARE pathway biosensor fish was generated and characterized, demonstrating spatiotemporal expression during early development. This transgenic fish shows responsiveness to Nrf2 pathway modulators and Edaravone, which has not been seen in any live transgenic fish models before. The activated reporter in this fish is also shown to be faithful during fin regeneration and slightly affected in a glucocerebrosidase morphant zebrafish model. Therefore, this innovative transgenic fish can serve as a valuable tool for studying zebrafish models of human diseases and primary high-throughput drug screening.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Lovisa Oerkenby, Signe Skog, Helen Ekman, Alessandro Gozzo, Unn Kugelberg, Rashmi Ramesh, Srivathsa Magadi, Gianluca Zambanini, Anna Nordin, Claudio Cantu, Daniel Naett, Anita Oest
Summary: Early-life stress can lead to long-term effects on adult health and disease risk, and this study reveals that these effects can be initiated in Drosophila embryos before the main wave of zygotic transcription. The researchers found that a short heat shock in early embryos resulted in changes in maternal miRNA and the expression of certain genes. They propose that maternal miRNAs, retained in response to an early embryonic heat shock, play a role in shaping the establishment of heterochromatin during early development.
MOLECULAR SYSTEMS BIOLOGY
(2023)
Article
Oncology
Toshiyasu Suzuki, Anna Kilbey, Nuria Casa-Rodriguez, Amy Lawlor, Anastasia Georgakopoulou, Hannah Hayman, Kyi Lai Yin Swe, Anna Nordin, Claudio Cantu, Pierre Vantourout, Rachel A. Ridgway, Ryan M. Byrne, Lei Chen, Michael P. Verzi, David M. Gay, Ester Gil Vazquez, Hayley L. Belnoue-Davis, Kathryn Gilroy, Anne Helene Kostner, Christian Kersten, Chanitra Thuwajit, Ditte K. Andersen, Robert Wiesheu, Anett Jandke, Karen Blyth, Antonia K. Roseweir, Simon J. Leedham, Philip D. Dunne, Joanne Edwards, Adrian Hayday, Owen J. Sansom, Seth B. Coffelt
Summary: Colon cancer cells evade immune surveillance by suppressing the expression of y8 T cells and Butyrophilin-like (BTNL) molecules. Reexpression of BTNL enhances the survival and activation of y8 T cells, but it does not affect their cancer-killing ability or recruitment to orthotopic tumors. However, inhibition of 13-catenin signaling through genetic deletion of Bcl9/Bcl9L restores the expression of Hnf4a, Hnf4g, and Btnl genes as well as infiltration of y8 T cells into tumors.
CANCER IMMUNOLOGY RESEARCH
(2023)
Article
Oncology
Simon Soderholm, Amaia Jauregi-Miguel, Pierfrancesco Pagella, Valeria Ghezzi, Gianluca Zambanini, Anna Nordin, Claudio Cantu
Summary: Wnt signaling activates the nuclear translocation of beta-catenin, which interacts with DNA-bound TCF/LEF transcription factors to regulate target gene specificity. However, the expression patterns of Wnt target genes do not always overlap. In this study, single-cell analysis revealed heterogeneity in the activation of Wnt target genes in human embryonic stem cells and other Wnt-responding cell types. The uncoupling of Wnt target gene expression suggests the presence of additional mechanisms that contribute to the diverse transcriptional outputs mediated by Wnt/beta-catenin signaling in single cells.
EXPERIMENTAL CELL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Giulia Nordio, Francesco Piazzola, Giorgio Cozza, Monica Rossetto, Manuela Cervelli, Anna Minarini, Filippo Basagni, Elisa Tassinari, Lisa Dalla Via, Andrea Milelli, Maria Luisa Di Paolo
Summary: Monoamine oxidases (MAOs) have been widely studied in neurological diseases, but recent research has discovered their potential role in certain types of cancer. This study identified novel MAO inhibitors with antiproliferative activity, suggesting their potential as anticancer agents.
Article
Biotechnology & Applied Microbiology
Anna Nordin, Gianluca Zambanini, Pierfrancesco Pagella, Claudio Cantu
Summary: CUT & RUN is a technique for mapping genome-wide binding profiles, but its unique biochemistry and data analysis methods result in undesired high-signal regions. This study analyzes CUT & RUN data from human and mouse genomes and finds that these problematic regions persist even after applying negative control and ENCODE blacklist removal. Experimental validation shows that these regions capture over 80% of the identified peaks. Therefore, removing these problematic regions is recommended to improve the reliability of CUT & RUN data.
Article
Biochemistry & Molecular Biology
Riccardo Rubbiani, Tobias Weil, Noemi Tocci, Luciano Mastrobuoni, Severin Jeger, Marco Moretto, James Ng, Yan Lin, Jeannine Hess, Stefano Ferrari, Andres Kaech, Luke Young, John Spencer, Anthony L. Moore, Kevin Cariou, Giorgia Renga, Marilena Pariano, Luigina Romani, Gilles Gasser
Summary: Fungal infections pose a global threat, especially for immunocompromised patients. The study focused on developing and characterizing novel organometallic derivatives of the frontline antifungal drug fluconazole, with one derivative showing significantly higher antifungal activity than fluconazole and effectiveness against clinical isolates. This finding highlights the potential of organometallic compounds in combating fungal infections and drug resistance.
RSC CHEMICAL BIOLOGY
(2021)
Article
Cell & Tissue Engineering
Miriam Pagin, Mattias Pernebrink, Simone Giubbolini, Cristiana Barone, Gaia Sambruni, Yanfen Zhu, Matteo Chiara, Sergio Ottolenghi, Giulio Pavesi, Chia-Lin Wei, Claudio Cantu, Silvia K. Nicolis
Summary: The Sox2 transcription factor is crucial for the long-term self-renewal of neural stem cells. The downstream molecule Fos plays a key role in maintaining cell proliferation, possibly through regulating the expression of Socs3. The findings suggest a network of interactions involving Sox2, Fos, and Socs3 in regulating NSC proliferation and maintenance.