Article
Pharmacology & Pharmacy
Jan Maly, Aiyana M. Emigh, Kevin R. DeMarco, Kazuharu Furutani, Jon T. Sack, Colleen E. Clancy, Igor Vorobyov, Vladimir Yarov-Yarovoy
Summary: The voltage-gated potassium channel hERG plays a crucial role in membrane repolarization of cardiac myocytes. By using Rosetta modeling, researchers investigated the conformational changes and drug binding mechanisms associated with hERG channel inactivation. The study provides insights into the structural changes and ligand interactions of hERG in the inactivated state.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Jing Li, Rong Shen, Bharat Reddy, Eduardo Perozo, Benoit Roux
Summary: This study investigates the structural and functional impacts of disease-associated mutations on C-type inactivation in the hERG channel using a combination of molecular dynamics simulations, free energy landscape calculations, and electrophysiological experiments. The results suggest that C-type inactivation is associated with a specific conformation of the selectivity filter, and that the degree of opening of the intracellular gate plays a key role in this process. Comparisons with other K+ channels indicate the importance of filter-gate allosteric coupling in C-type inactivation.
Article
Pharmacology & Pharmacy
Aiyana M. Emigh Cortez, Kevin R. Demarco, Kazuharu Furutani, Slava Bekker, Jon T. Sack, Heike Wulff, Colleen E. Clancy, Igor Vorobyov, Vladimir Yarov-Yarovoy
Summary: The human ether-a-go-go-related gene (hERG) is crucial for normal electrical activity in the heart but can also be targeted by drugs. This study utilized computational methods to build structural models of hERG channel in different conformational states and investigated the interactions between drugs and the channel. The findings provide important insights into differentiating safe and harmful hERG blockers based on their structural interactions.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Victoria Amstrup Vold, Sebastian Glanville, Dan Arne Klaerke, Per Amstrup Pedersen
Summary: In order to solve the problem of obtaining sufficient ultra-pure protein for structural studies of membrane proteins, a dual-function plasmid, pXOOY, was constructed for protein production in yeast and electrophysiology in oocytes. The plasmid combines elements from a Xenopus-mammalian vector and a high-yield yeast expression vector. The performance of pXOOY was evaluated and it was found that it led to higher accumulation of the expressed channels in yeast cells and maintained channel activity in oocytes.
Article
Biochemistry & Molecular Biology
Shruti Koulgi, Vinod Jani, Vinay Nair, Jagmohan S. Saini, Samiron Phukan, Uddhavesh Sonavane, Rajendra Joshi, Raj Kamboj, Venkata Palle
Summary: Evaluation of cardiotoxicity potential of new chemical entities has become a stringent filter in drug discovery, with a focus on hERG channel protein inhibition. A computational model for the active-state of hERG was developed and showed noticeable conformational changes in the protein upon ligand-binding, potentially leading to a collapse of the pore and transition of hERG from an open to an inactive state. These findings could aid in designing compounds devoid of hERG inhibition and reduced cardiotoxicity.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biology
Jinyuan Vero Li, Chai-Ann Ng, Delfine Cheng, Zijing Zhou, Mingxi Yao, Yang Guo, Ze-Yan Yu, Yogambha Ramaswamy, Lining Arnold Ju, Philip W. Kuchel, Michael P. Feneley, Diane Fatkin, Charles D. Cox
Summary: The N-linked glycosylation of mechanosensitive ion channel Piezo1 plays a crucial role in its function, with disease-linked mutant variants showing a lack of N-linked glycosylation. This deficiency affects protein trafficking, highlighting the importance of N-glycosylation in membrane trafficking.
COMMUNICATIONS BIOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Cedric Dzidzor Kodjo Amengor, Emmanuel Orman, Cynthia Amaning Danquah, Inemesit Okon Ben, Prince Danan Biniyam, Benjamin Kingsley Harley
Summary: In this study, pyridine-N-oxide alkaloids from Allium stipitatum and their synthetic disulfide analogs were investigated as potential next-generational antimycobacterial agents. In silico studies, molecular docking simulations, and molecular descriptor analysis were conducted to determine their binding affinities and properties. The results suggested that these compounds have strong binding affinities and favorable properties, making them promising lead candidates for the treatment of multidrug-resistant tuberculosis.
BIOMED RESEARCH INTERNATIONAL
(2022)
Article
Chemistry, Analytical
Tingting Pan, Min Shen, Jiayan Shi, Juewei Ning, Fengyu Su, Jianxiang Liao, Yanqing Tian
Summary: Researchers developed K+ fluorescent nanoprobes for intracellular K+ sensing and imaging, and constructed an easy-operating and biocompatible method for measuring human ether-a-go-go-related gene (hERG) channel activity. This method was efficient for screening hERG channel inhibitors and imaging K+ channel activity in cancer cells.
SENSORS AND ACTUATORS B-CHEMICAL
(2021)
Article
Chemistry, Medicinal
Qianqian Liang, Zhen Qiao, Qiqi Zhou, Dengqi Xue, KeWei Wang, Liming Shao
Summary: This study reports the synthesis of N-indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. Compound 28 is identified as a potent and selective TRPV1 agonist, relieving inflammatory and thermal pain by desensitizing the native TRPV1 current in mice. The study also reveals an important hydrogen interaction between Arg557 and the indazole of compound 28.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Pascal Champeroux, Raafat Fares, Thierry Bastogne, Serge Richard, Jean-Yves Le Guennec, Jerome Thireau
Summary: This study reveals the underlying mechanisms of ventricular arrhythmias triggered by Torsadogenic HERG blocking drugs. The autonomic changes induced by these drugs are a result of reflex compensatory mechanisms in response to mild haemodynamic side effects. Concealed QT prolongation, along with enhanced HFQT oscillations, contribute to the occurrence of ventricular arrhythmias.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Jarvis Hill, Robert M. Jones, David Crich
Summary: This study describes an atypical amine bioisostere, the trisubstituted hydroxylamine, which, when incorporated into an approved dual cSRC/BCR-ABL1 kinase inhibitor, produces compound 9 with potent biological activity and improved drug efflux and hERG affinity. Contrary to the common expectation for hydroxylamines in medicinal chemistry, compound 9 is well tolerated in vivo and does not exhibit mutagenicity and genotoxicity. The beneficial properties of the N-alkyl to N-noralkoxy switch in compound 9 appear to be attributed to a reduction in basicity of the piperazine unit.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Fumiya Tamura, Shintaro Sugimoto, Mana Sugimoto, Kazuho Sakamoto, Masahiko Yamaguchi, Takeshi Suzuki, Keiichi Fukuda, Masaki Ieda, Junko Kurokawa
Summary: The synthetic estrogen ethinylestradiol (EE2) did not significantly affect hERG currents at supratherapeutic concentrations but reduced the degree of hERG current suppression by E-4031 at therapeutic concentrations. The findings suggest a potential interaction between EE2 and E-4031 altering hERG function at the drug-binding site.
Article
Chemistry, Medicinal
Katarzyna Grychowska, Agnieszka Olejarz-Maciej, Klaudia Blicharz, Wojciech Pietrus, Tadeusz Karcz, Rafal Kurczab, Paulina Koczurkiewicz, Agata Doroz-Plonka, Gniewomir Latacz, Abdul Raheem Keeri, Kamil Piska, Grzegorz Satala, Joanna Pegiel, Wojciech Trybala, Magdalena Jastrzebska-Wiesek, Andrzej J. Bojarski, Frederic Lamaty, Anna Partyka, Maria Walczak, Martyna Krawczyk, Natalia Malikowska-Racia, Piotr Popik, Pawel Zajdel
Summary: The incorporation of fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines led to the identification of a reversible MAO-B inhibitor, compound 26, which exhibited selectivity, anti-targeting effects, potent glioprotective properties, and favorable metabolic stability and brain permeability. Compound 26 also demonstrated procognitive effects and antidepressant-like activity, suggesting potential therapeutic applications in Alzheimer's disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Kazuharu Furutani
Summary: Modulating the hERG channel has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. Recent research has shown that certain antiarrhythmic drugs not only block the hERG channel, but also facilitate its activation, which reduces the proarrhythmic potential.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Gaia Pasqualetto, Marika Zuanon, Andrea Brancale, Mark T. Young
Summary: P2X receptors are ATP-gated cation channels that play key roles in nerve transmission, pain sensation, and inflammation. P2X4 receptor has attracted interest from pharmaceutical companies due to its roles in neuropathic pain and vascular tone modulation. A study confirmed the importance of a specific amino acid (I312T) for the sensitivity of the P2X4 receptor antagonist BX430 and identified a plausible binding pocket for a series of P2X4 antagonists.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)