Article
Biology
Xingang Liu, Wenying Yan, Songsong Wang, Ming Lu, Hao Yang, Xu Chai, He Shi, Yang Zhang, Qingzhong Jia
Summary: A multi-layer virtual screening workflow was established to screen compounds with inhibitory activity against HDAC6 and anti-tumor cell proliferation. The screened compounds showed nanomolar inhibitory activity and anti-proliferative activities against tumor cells, providing novel scaffolds for subsequent anti-tumor drug design based on HDAC6 target.
COMPUTERS IN BIOLOGY AND MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
P. M. Gurubasavaraja Swamy, Nahid Abbas, Prasad Sanjay Dhiwar, Ekta Singh, Abhishek Ghara, Arka Das
Summary: In this study, a 3D QSAR pharmacophore model was generated using substituted pyrimidine class of Aurora-A kinase inhibitors, revealing the crucial role of molecular features in inhibitory activity. Five potential compounds were identified through screening and docking, demonstrating their distinctive ability to inhibit Aurora-A kinase.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Physical
Dong Zhao, Antal H. Kovacs, Michael Campbell, Wely Floriano, Jinqiang Hou
Summary: In this study, the selective binding mechanism of Barasertib, a ligand with high selectivity for Aurora kinase B over A, was investigated through molecular dynamics simulations and binding free energy analyses. The results showed that the hinge residue Arg159 in Aurora kinase B played a crucial role in Barasertib binding, and the binding interactions at the hydrophobic back pocket were important for the selectivity. The insights into the structural determinants of subtype selectivity will contribute to the development of selective Aurora kinase B inhibitors for cancer therapy.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Article
Chemistry, Medicinal
Xiaoyi Zhang, Yifan Yang, Yuji Wang, Jianhui Wu, Qiongyan Fang, Ming Zhao, Yaonan Wang, Shiqi Peng
Summary: The combination of virtual screening and biological assays led to the discovery of 4j as a promising candidate of selective inhibitor of thrombin.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Janek Szychowski, Robert Papp, Evelyne Dietrich, Bingcan Liu, Frederic Vallee, Marie-Eve Leclaire, Jimmy Fourtounis, Giovanni Martino, Alexander L. Perryman, Victor Pau, Shou Yun Yin, Pavel Mader, Anne Roulston, Jean-Francois Truchon, C. Gary Marshall, Mohamed Diallo, Nicole M. Duffy, Rino Stocco, Claude Godbout, Alexanne Bonneau-Fortin, Rosie Kryczka, Vivek Bhaskaran, Daniel Mao, Stephen Orlicky, Patrick Beaulieu, Pascal Turcotte, Igor Kurinov, Frank Sicheri, Yael Mamane, Michel Gallant, W. Cameron Black
Summary: PKMYT1 acts as a regulator of CDK1 phosphorylation and has been identified as a potential therapeutic target for certain types of DNA damage response cancers. In this study, a weak inhibitor of PKMYT1 was identified and further optimized using structure-based drug design to improve its potency. The resulting potent and selective inhibitors, such as RP 6306, showed inhibitory effects on CCNE1-amplified tumor cell growth in preclinical xenograft models. RP 6306 is currently being evaluated in Phase 1 clinical trials for the treatment of various solid tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Kisa Sung, Agata Kurowski, Carisse Lansiquot, Kanny K. Wan, Samarjit Patnaik, Martin J. Walsh, Michael B. Lazarus
Summary: This study uncovers a link between autophagy and cell cycle progression and explores the inhibition of autophagy in pancreatic cancer cells using selective small molecule inhibitors. Additionally, new combination treatments were discovered through an unbiased screen.
ACS CHEMICAL BIOLOGY
(2022)
Article
Oncology
Hiroshi Hongo, Takeo Kosaka, Yoko Suzuki, Mototsugu Oya
Summary: Pimozide appears to be a promising drug to overcome docetaxel-resistant castration-resistant prostate cancer (CRPC) by targeting AURKB and KIF20A.
PROSTATE CANCER AND PROSTATIC DISEASES
(2023)
Article
Chemistry, Medicinal
Jing Guo, Shuang Xiang, Jie Wang, Yang Zhou, Zuqin Wang, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of tumors and chronic pain. This study discovered a novel TrkA allosteric inhibitor through structure-based virtual screening and conducted preliminary research on its properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xiaofei Liang, Chun Wang, Beilei Wang, Juan Liu, Shuang Qi, Aoli Wang, Qingwang Liu, Maoqing Deng, Li Wang, Jing Liu, Qingsong Liu
Summary: CSF1R kinase is crucial in tumor-associated macrophage repolarization, and the selective inhibitor 18h shows potent inhibition against CSF1R with significant selectivity, leading to suppression of tumor growth.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Tony Eight Lin, Chia-Ron Yang, Ching-Hsuan Chou, Jui-Yi Hsu, Min-Wu Chao, Tzu-Ying Sung, Jui-Hua Hsieh, Wei-Jan Huang, Kai-Cheng Hsu
Summary: Research has identified new CDK8 inhibitors with potential in reducing the expression of inflammatory signaling mediators and low cytotoxicity in cell lines. One compound, F059-1017, showed higher selectivity and potency towards CDK8, making it a potential lead compound for developing novel anti-inflammatory therapeutics.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Pharmacology & Pharmacy
Huizhen Ge, Lizeng Peng, Zhou Sun, Huanxiang Liu, Yulin Shen, Xiaojun Yao
Summary: In this study, novel HPK1 inhibitors were identified using virtual screening and kinase inhibition assays. Molecular dynamics simulations were performed to analyze the interaction between the identified compounds and HPK1 kinase domain. The most potent compound showed potential for further development as an HPK1 inhibitor for immunotherapy.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Jingyu Zhu, Kan Li, Lei Xu, Yanfei Cai, Yun Chen, Xinling Zhao, Huazhong Li, Gang Huang, Jian Jin
Summary: A novel machine learning-based virtual screening model was developed to discover new PI3K gamma inhibitors. Among the identified inhibitors, JN-K13 displayed selective cytotoxicity on hematologic tumor cells at low concentrations and promoted apoptosis through the inhibition of PI3K signaling. This study suggests that PI3K gamma could be a potential target for hematologic tumor therapy.
JOURNAL OF ADVANCED RESEARCH
(2022)
Article
Chemistry, Medicinal
Tiancheng Fu, Yingying Zuo, Zhenpeng Zhong, Xuan Chen, Zhengying Pan
Summary: In this study, a novel series of selective and irreversible inhibitors of BLK were discovered, showing potent antiproliferative activities against several B-cell lymphoma cell lines. These compounds represent the first selective inhibitors developed for BLK, which could expedite the exploration of BLK functions.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Pengxing He, Jing Jing, Linna Du, Xuyang Zhang, Yufei Ren, Han Yang, Bin Yu, Hongmin Liu
Summary: YS-363 is a novel EGFR inhibitor that demonstrates potent reversible inhibition and excellent activities against cell proliferation, migration, cell cycle and apoptosis. It is a promising selective inhibitor that can potentially be developed as a more effective anti-lung cancer agent targeting EGFR.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Shuaishuai Xing, Ying Chen, Baichen Xiong, Weixuan Lu, Qi Li, Yuanyuan Wang, Mengxia Jiao, Feng Feng, Yao Chen, Wenyuan Liu, Haopeng Sun
Summary: 2513-4169, a promising lead compound, shows potential inhibitory activity and neuroprotective effect for treating Alzheimer's disease.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Cell Biology
Alexandra Bezler, Alexander Woglar, Fabian Schneider, Friso Douma, Leo Buergy, Coralie Busso, Pierre Goenczy
Summary: The study finds that there can be unexpected plasticity in the number of microtubules between centrioles and axonemes.
MOLECULAR BIOLOGY OF THE CELL
(2022)
Article
Biochemistry & Molecular Biology
Anastassia L. Kantsadi, Georgios N. Hatzopoulos, Pierre Gonczy, Ioannis Vakonakis
Summary: Centrioles are eukaryotic organelles that play important roles in cellular processes like cilia and flagella formation, microtubule network organization, and mitotic spindle assembly. This research reveals that the asymmetric interaction mediated by the coiled-coil domain of SAS-6 is crucial for the assembly and polarity of the centriolar central scaffold, the cartwheel. Disrupting this asymmetric interaction impairs the stacking of SAS-6 rings. These findings provide new insights into the assembly of centrioles and cell division.
Article
Chemistry, Medicinal
Elena Zakharova, Markus Orsi, Alice Capecchi, Jean-Louis Reymond
Summary: This study successfully discovered new non-hemolytic anticancer peptides using recurrent neural networks and machine learning methods, demonstrating the first application of machine learning in this field.
Article
Cell Biology
Shrividya Sana, Ashwathi Rajeevan, Sachin Kotak
Summary: The exclusive localization of NuMA and Ect2/Cyk4/Mklp1 ensures the coordination of spindle elongation and cleavage furrow formation. This coordination is achieved by restricting dynein/dynactin and RhoA to distinct membrane zones.
JOURNAL OF CELL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Johannes Morstein, Alice Capecchi, Konstantin Hinnah, ByungUk Park, Jerome Petit-Jacques, Reid C. Van Lehn, Jean-Louis Reymond, Dirk Trauner
Summary: Most bioactive molecules need to cross or be distributed into biological membranes, and natural products often have lipid modifications to facilitate molecule-membrane interactions. Lipidated natural products primarily contain saturated medium-chain lipids, and lipid conjugation can significantly modulate the permeability, cellular retention, subcellular localization, and bioactivity of small molecules.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Valentina Rossetti, Jean-Louis Reymond
Summary: In this article, we share the aims, development, challenges, and outcome of the National Center of Competence in Research (NCCR) TransCure's temporary learning and artistic path called 'Vitaport - Was unser Korper transpor-tiert' in Bern. This project involved NCCR TransCure researchers and students from the Bern School of Design, who developed ceramic objects, texts, and information graphics to take the public on a multidisciplinary journey through the human body.
Article
Chemistry, Multidisciplinary
Tin Manh Ho, Stephan Berger, Philipp Mueller, Celine Simonin, Jean-Louis Reymond, Christoph von Ballmoos, Daniel G. Fuster
Summary: The goal of this research was to investigate the physiological and molecular function of NHA2, develop a high resolution kinetic transport assay, and identify specific compounds targeting NHA2. The interdisciplinary and interfaculty effort led to successful results and provided important information for further research and drug development.
Article
Chemistry, Medicinal
Ye Buehler, Jean-Louis Reymond
Summary: The generated databases (GDBs) list billions of possible molecules through systematic enumeration following simple rules of chemical stability and synthetic feasibility. The originality of GDB molecules can be assessed by comparing their Bemis and Murcko molecular frameworks (MFs) with those in public databases. This comparison revealed that GDB-13s MFs had diverse ring sizes and ring systems without linker bonds, making them attractive targets for synthetic chemistry aiming at innovative molecules.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Joel S. Bloch, Alan John, Runyu Mao, Somnath Mukherjee, Jeremy Boilevin, Rossitza N. Irobalieva, Tamis Darbre, Nichollas E. Scott, Jean-Louis Reymond, Anthony A. Kossiakoff, Ethan D. Goddard-Borger, Kaspar P. Locher
Summary: C-linked glycosylation is essential for the trafficking, folding, and function of secretory and transmembrane proteins involved in cellular communication processes. Cryogenic-electron microscopy structures of Caenorhabditis elegans CMT reveal how the CMT recognizes the glycosylation sequon and triggers conformational activation of the donor substrate, enabling C-glycosylation of proteins. These findings have implications for understanding human diseases and potential therapeutic targeting of specific CMT paralogs.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Hippolyte Personne, Thissa N. Siriwardena, Sacha Javor, Jean-Louis Reymond
Summary: Here, we demonstrate that dipropylamine (DPA) can effectively reduce aspartimide formation in high-temperature solid-phase peptide synthesis (SPPS) compared to piperidine (PPR). DPA is easily accessible, inexpensive, non-toxic, and odorless, making it a promising alternative to PPR. Furthermore, DPA yields good results in SPPS of non-aspartimide-prone peptides and peptide dendrimers.
Article
Chemistry, Multidisciplinary
Etienne Bonvin, Jean-Louis Reymond
Summary: We redesigned the branches of PAMAM dendrimers to improve their stability by modifying the amide carbonyl group. The resulting i-PAMAM dendrimers have the same carbon framework as PAMAMs but differ in the position of the carbonyl group. Compared to PAMAMs, which are difficult to purify, we synthesized i-PAMAMs using solid-phase peptide synthesis and purified them using preparative reverse phase HPLC. Our i-PAMAM dendrimers showed no degradation over time and exhibited potent antimicrobial activities against both Gram-negative and Gram-positive bacteria.
HELVETICA CHIMICA ACTA
(2023)
Article
Chemistry, Multidisciplinary
Matheus A. Meirelles, Jean-Louis Reymond
Summary: This study presents an optimized synthesis method for a probe used in studying protein N-glycosylation in eukaryotic cells. The yields and reaction times of three phosphate coupling steps were improved by adjusting reagents and conditions. An efficient purification protocol was also developed to obtain the pure product.
HELVETICA CHIMICA ACTA
(2023)
Article
Chemistry, Medicinal
Ye Buehler, Jean-Louis Reymond
Summary: Identifying novel ring fragments (RFs) and acyclic fragments (AFs) from public databases and natural products can provide potential opportunities for drug innovation in fragment-based drug discovery.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Etienne Bonvin, Hippolyte Personne, Thierry Paschoud, Jeremie Reusser, Bee-Ha Gan, Alexandre Luscher, Thilo Kohler, Christian van Delden, Jean-Louis Reymond
Summary: By introducing peptoid units into antimicrobial peptides, the antimicrobial effects can be retained with reduced toxicity to human cells, and under specific conditions, there may be a transition towards intracellular targeting.
ACS INFECTIOUS DISEASES
(2023)
Article
Chemistry, Multidisciplinary
David Kreutter, Jean-Louis Reymond
Summary: This study introduces a new tool for computer-aided synthesis planning that can automatically learn organic reactivity and perform retrosynthesis. The tool combines a triple transformer loop and a multistep tree search algorithm to propose short synthetic routes based on commercial starting materials.