Article
Chemistry, Medicinal
Ilyas Berhane, Niyada Hin, Ajit G. Thomas, Qian Huang, Chi Zhang, Vijayabhaskar Veeravalli, Ying Wu, Justin Ng, Jesse Alt, Camilo Rojas, Hiroe Hihara, Mika Aoki, Kyoko Yoshizawa, Tomoki Nishioka, Shuichi Suzuki, Shao-Qiu He, Qi Peng, Yun Guan, Xinzhong Dong, Srinivasa N. Raja, Barbara S. Slusher, Rana Rais, Takashi Tsukamoto
Summary: A orally available positive allosteric modulator of MRGPRX1 has been discovered, which shows potential in treating neuropathic pain.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jianfang Fu, Jie Yu, Xiang Zhang, Yaoyao Chang, Hongze Fan, Mengzhen Dong, Mengjia Li, Yue Liu, Jinxing Hu
Summary: In this study, two series of EGFR kinase inhibitors were designed and synthesised. Compound B1 showed selective inhibition against EGFR (L858R/T790M) with an IC50 value of 13 nM and a 76-fold selectivity for EGFR (WT). In vitro experiments demonstrated that compound B1 effectively inhibited proliferation of H1975 cells with an IC50 value of 0.087 μM. Mechanistic studies confirmed the selective inhibition of EGFR (L858R/T790M) by compound B1 through cell migration and apoptosis assays.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Inorganic & Nuclear
Tong Jian-Bo, Feng Yi, Wang Tian-Hao, Zhang Xing
Summary: In this study, CoMFA, CoMSIA, and HQSAR techniques were utilized to investigate the important characteristic activities of thieno [2,3-d] pyrimidine derivatives for effective antitumor activity. Molecular docking was also employed to study the binding requirements between ligands and receptor proteins, showing promising results that can be used for designing anticancer drugs.
CHINESE JOURNAL OF STRUCTURAL CHEMISTRY
(2021)
Article
Chemistry, Physical
Tianshuai Wang, Fengxu Wu, Lun Luo, Yan Zhang, Junkai Ma, Yanggen Hu
Summary: The fused heterocyclic ring system of thienopyrimidine scaffold has been widely used in pharmaceuticals to enhance pharmacological and biological activities. In this study, polysubstituted thieno[2,3-d]pyrimidine derivatives were synthesized and tested for their cytotoxic activity against Hela and A549 cancer cell lines. Compound 8c showed promising activity similar to the lead drug Olmutinib, and its binding to EGFR kinase differed from Olmutinib. The preliminary structure-activity relationship suggested that introducing oxygen substituents favored antitumor activity.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Biochemistry & Molecular Biology
Yan Sun, Rong Fu, Songwen Lin, Jingbo Zhang, Ming Ji, Yan Zhang, Deyu Wu, Kehui Zhang, Hua Tian, Mingyi Zhang, Li Sheng, Yan Li, Jing Jin, Xiaoguang Chen, Heng Xu
Summary: A new series of PI3K inhibitors were designed and synthesized, showing promising anti-cancer activity and in vivo efficacy. Among them, thiazolo [5,4-d]pyrimidine 7a demonstrated superior anti-cancer activity compared to other compounds, warranting further pre-clinical evaluation.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Rongcai Ding, Xiaoxia Wang, Jianfang Fu, Yaoyao Chang, Yingxue Li, Yajing Liu, Yue Liu, Jinlong Ma, Jinxing Hu
Summary: A series of novel pleuromutilin derivatives with substituted thienopyrimidines were designed, synthesized, and evaluated for their antibacterial activity. Most of the compounds exhibited moderate antibacterial activity against Staphylococcus aureus, Streptococcus agalactiae, and Escherichia coli. Compound A11 showed the most activity and displayed bacteriostatic activities against methicillin-resistant S. aureus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Mahmoud S. Tolba, Ahmed M. Sayed, Mostafa Sayed, Mostafa Ahmed
Summary: A synthetic method for designing new thienopyrimidines was presented, with spectral analysis confirming the structures of all synthesized compounds. The compounds showed significant antibacterial and anti-inflammatory activity compared to standard drugs, and molecular docking was used to investigate their mechanisms. Drug-like properties were analyzed for potential oral drug candidates.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Biochemistry & Molecular Biology
Rasha A. Hassan, Mohammed I. A. Hamed, Amr M. Abdou, Yara El-Dash
Summary: In this study, a series of thieno[2,3-d]pyrimidine derivatives were designed and synthesized. These compounds showed significant antiproliferative activity, potent inhibitory effects on VEGFR-2 and BRAF, reduced cell migration, induced apoptosis, and arrested the cell cycle in G1 and G1/S phases. The findings suggest their potential as multitargeted anticancer agents.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Olga Riabova, Anna Egorova, Alexander Lepioshkin, Yan Li, Kerstin Voigt, Florian Kloss, Vadim Makarov
Summary: Thieno[2,3-d]pyrimidines represent a novel antibacterial prodrug scaffold with potential antibacterial effects against Gram-positive bacteria, particularly Staphylococci (MRSA). The two most promising hit compounds demonstrate good pharmacokinetic properties in vitro and acceptable toxicity, qualifying them as starting points for lead-generation campaigns.
Review
Chemistry, Organic
Ankita Chaudhary
Summary: Pyrido[2,3-d]pyrimidines play a significant role in medicinal chemistry due to their diverse biological activities, and their synthesis is an ongoing area of research. Constructing biologically relevant moieties through a multicomponent approach is a promising research direction, driven by the increasing emphasis on 'green chemistry'.
CURRENT ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Haibo Lu, Tian Lu, Shijia Zu, Zhe Duan, Yiman Guang, Qi Li, Jingyi Ma, Dongying Chen, Bo Li, Wenchao Lu, Hualiang Jiang, Cheng Luo, Deyong Ye, Kaixian Chen, Hua Lin
Summary: This study reports the discovery of a series of CECR2 BRD inhibitors and identifies DC-CBi-22 as the most potent compound. DC-CBi-22 exhibits strong inhibitory activity against CECR2 BRD and shows selectivity over BPTF BRD. This finding is important for the study of CECR2.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Richard agren, Kristoffer Sahlholm
Summary: SB269,652 is the first negative allosteric modulator of the dopamine D-2 receptor, but its mechanism of action is not fully understood. This study investigated the interaction between dopamine and SB269,652 and found that the inhibitory potency of SB269,652 is greatly increased after ligand pre-incubation. Mutagenesis experiments suggested that specific amino acids in the orthosteric binding site and the secondary binding pocket are involved in this effect. These findings expand our knowledge of how SB269,652 competes with dopamine at the D2R and could be important for the development of new D2R ligands.
Article
Biochemistry & Molecular Biology
Souad A. El-Metwally, Mohsen M. Abou-El-Regal, Ibrahim H. Eissa, Ahmed B. M. Mehany, Hazem A. Mahdy, Hazem Elkady, Alaa Elwan, Eslam B. Elkaeed
Summary: Novel thieno[2,3-d]pyrimidine derivatives with structural similarity to VEGFR-2 inhibitors were designed and synthesized, showing promising anticancer activities against human cancer cell lines. Compound 17f exhibited the highest cytotoxic activities against HCT-116 and HepG2 cell lines and displayed high inhibitory activity against VEGFR-2, comparable to the reference drug sorafenib. ADMET and toxicity assessments revealed that most compounds had low BBB penetration levels and were non-toxic, except for compounds 17b and 20b.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Souad A. El-Metwally, Hazem Elkady, Mohamed Hagras, Eslam B. Elkaeed, Bshra A. Alsfouk, Ahmed S. Doghish, Ibrahim M. Ibrahim, Mohammed S. Taghour, Dalal Z. Husein, Ahmed M. Metwaly, Ibrahim H. Eissa
Summary: This study developed thieno[2,3-d]pyrimidine derivatives as potential anti-cancer agents targeting VEGFR-2. Compound 10d demonstrated strong anti-cancer potential by boosting apoptosis through VEGFR-2 inhibition. These compounds have good binding affinities to VEGFR-2 and may contribute to the development of new anticancer therapies.
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Yuehua Zhang, Zhaoping Pan, Can Chen, Yiwei Tan, Xiaoyun Wang, Lian Wang, Lu Zhang, Yi Chen, Gu He
Summary: By utilizing a multifunctional drug development strategy, new derivatives of BRD4 inhibitors capable of releasing nitric oxide were designed and synthesized, demonstrating excellent antitumor activity and inducing cellular apoptosis and autophagic cell death. This approach holds potential for targeted therapy in ovarian cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Yuni Kay, Linda Tsan, Elizabeth A. Davis, Chen Tian, Lea Decarie-Spain, Anastasiia Sadybekov, Anna N. Pushkin, Vsevolod Katritch, Scott E. Kanoski, Bruce E. Herring
Summary: Mutations in the putative glutamatergic synapse scaffolding protein SAP97 can enhance glutamatergic synapse strength in the dentate gyrus, impairing contextual episodic memory in rats.
NATURE COMMUNICATIONS
(2022)
Article
Cardiac & Cardiovascular Systems
Chongzhe Yang, Jie Li, Zhiyong Deng, Songyuan Luo, Jing Liu, Wenqian Fang, Feng Liu, Tianxiao Liu, Xian Zhang, Yuanyuan Zhang, Zhaojie Meng, Shuya Zhang, Jianfang Luo, Conglin Liu, Dafeng Yang, Lijun Liu, Galina K. Sukhova, Anastasiia Sadybekov, Vsevolod Katritch, Peter Libby, Jing Wang, Junli Guo, Guo-Ping Shi
Summary: This study explored the role of blood eosinophil counts and eosinophil cationic protein (ECP) levels in cardiac hypertrophy. It revealed positive correlations between blood eosinophil counts and left ventricular mass in humans. Further experiments in mice showed that eosinophil deficiency exacerbated cardiac hypertrophy and dysfunction. The study also demonstrated that repopulation of eosinophils from wild-type mice improved cardiac hypertrophy. Mechanistic studies revealed that eosinophil expression of IL4, IL13, and mEar1 were essential in controlling cardiomyocyte hypertrophy and death, as well as fibroblast TGF-beta signaling and fibrotic protein synthesis. The use of human cardiac cells yielded similar results. The study suggests a cardioprotective role for eosinophils and ECP in cardiac hypertrophy and highlights the therapeutic potential of ECPs in cardiovascular disease.
CARDIOVASCULAR RESEARCH
(2023)
Article
Chemistry, Medicinal
Zhi Yuan Kok, Leigh A. Stoddart, Sarah J. Mistry, Tamara A. M. Mocking, Henry F. Vischer, Rob Leurs, Stephen J. Hill, Shailesh N. Mistry, Barrie Kellam
Summary: This study reports a series of high-affinity H1R fluorescent ligands, which overcome the limitations of linker SAR by incorporating a BODIPY 630/650-based fluorophore, and successfully visualizes HA at a concentration of 10 nM using confocal microscopy.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Michael J. Cunningham, Hailey A. Bock, Inis C. Serrano, Benjamin Bechand, D. J. Vidyadhara, Emma M. Bonniwell, David Lankri, Priscilla Duggan, Antonina L. Nazarova, Andrew B. Cao, Maggie M. Calkins, Prashant Khirsariya, Christopher Hwu, Vsevolod Katritch, Sreeganga S. Chandra, John D. McCorvy, Dalibor Sames
Summary: Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that has been tested in humans, showing therapeutic effects such as remission of psychotic symptoms and improved cognition. It acts as a serotonin 5-HT2 receptor agonist with modest selectivity over 5-HT1 receptors. Compared to its hallucinogenic analog, Ariadne exhibits lower signaling potency and efficacy in multiple signaling pathways. It has considerable therapeutic potential across psychiatric and neurological indications.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Multidisciplinary Sciences
Abdelfattah Faouzi, Haoqing Wang, Saheem A. Zaidi, Jeffrey F. DiBerto, Tao Che, Qianhui Qu, Michael J. Robertson, Manish K. Madasu, Amal El Daibani, Balazs R. Varga, Tiffany Zhang, Claudia Ruiz, Shan Liu, Jin Xu, Kevin Appourchaux, Samuel T. Slocum, Shainnel O. Eans, Michael D. Cameron, Ream Al-Hasani, Ying Xian Pan, Bryan L. Roth, Jay P. McLaughlin, Georgios Skiniotis, Vsevolod Katritch, Brian K. Kobilka, Susruta Majumdar
Summary: Researchers have developed a new approach to design safer therapeutic agents by targeting a conserved sodium ion-binding site in mu-opioid receptors. Cryo-electron microscopy structures revealed the key interactions between the ligands and the binding site, leading to the development of potent ligands with reduced adverse effects. This study highlights the potential of targeting the sodium ion-binding site for the design of safer analgesics and suggests that engagement of this site can control the efficacy and selectivity profiles of G-protein-coupled receptors.
Article
Biochemistry & Molecular Biology
Dongqi Zhang, Yongfeng Liu, Saheem A. Zaidi, Lingyi Xu, Yuting Zhan, Anqi Chen, Jiangtao Guo, Xi-Ping Huang, Bryan L. Roth, Vsevolod Katritch, Vadim Cherezov, Haitao Zhang
Summary: The cryo-EM structure of human AT(1)R complexed with Sar(1)-AngII and G(q) protein reveals the molecular mechanisms of AT(1)R signaling modulation and biased signaling induced by mutations in the major hydrogen bond network. These findings have implications for drug discovery in cardiovascular diseases.
Article
Chemistry, Medicinal
Sebastian Dekkers, Birgit Caspar, Joelle Goulding, Nicholas D. Kindon, Laura E. Kilpatrick, Leigh A. Stoddart, Stephen J. Briddon, Barrie Kellam, Stephen J. Hill, Michael J. Stocks
Summary: In this study, fluorescent probes based on previously reported small-molecule antagonists were designed and synthesized using classic medicinal chemistry approaches to investigate the pharmacology and cellular distribution of the CXCR4 receptor. Three distinct chemical classes of fluorescent probes were developed and shown to specifically bind to the CXCR4 receptor in a fluorescence-based NanoBRET binding assay (pKD ranging 6.6-7.1). These probes were also used in competition binding experiments and confocal microscopy to further explore the pharmacology and cellular distribution of CXCR4.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Multidisciplinary Sciences
Anastasiia V. Sadybekov, Vsevolod Katritch
Summary: Computer-aided drug discovery has experienced a significant shift towards computational technologies for efficient ligand screening. This shift is driven by the availability of vast ligand data, abundant computing capacities, and virtual libraries of drug-like small molecules. Recent advances in deep learning predictions of ligand properties and target activities, as well as structure-based virtual screening, have the potential to reshape the drug discovery and development process. The rapid identification of diverse, potent, target-selective, and drug-like ligands to protein targets can democratize the drug discovery process, enabling cost-effective development of safer and more effective treatments.
Article
Multidisciplinary Sciences
Amal El Daibani, Joseph M. M. Paggi, Kuglae Kim, Yianni D. D. Laloudakis, Petr D. Popov, Sarah M. M. Bernhard, Brian E. E. Krumm, Reid H. J. Olsen, Jeffrey Diberto, F. Ivy Carroll, Vsevolod Katritch, Bernhard Wuensch, Ron O. O. Dror, Tao Che
Summary: Using structural determination, molecular dynamics simulations, and functional assays, the researchers identified molecular determinants of KOR signaling bias. They determined the crystal structure of KOR bound to the G protein-biased agonist nalfurafine and identified an arrestin-biased KOR agonist, WMS-X600. Through simulations and mutagenesis validation, they explained how agonists achieve biased signaling at KOR.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Yasmin Aydin, Thore Bottke, Jordy Homing Lam, Stefan Ernicke, Anna Fortmann, Maik Tretbar, Barbara Zarzycka, Vsevolod V. Gurevich, Vsevolod Katritch, Irene Coin
Summary: Understanding the molecular basis of arrestin-mediated regulation of GPCRs is crucial for deciphering signaling mechanisms. However, structural studies are challenging due to the dynamic nature of GPCR-arrestin complexes. In this study, the interaction between arrestin-2 and PTH1R was dissected using crosslinking amino acids in live cells. The integrative approach revealed the structure, dynamics, and flexible regions of the PTH1R-arrestin2 complex.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Rob Hill, Julie Sanchez, Laura Lemel, Mirjana Antonijevic, Yselkla Hosking, Shailesh N. Mistry, Andrew C. Kruegel, Jonathan A. Javitch, J. Robert Lane, Meritxell Canals
Summary: This study evaluated the effects of three novel opioids on respiratory depression and analgesia, and compared these measurements with their in vitro efficacy. The results showed that these opioids can induce respiratory depression and analgesia at certain doses, but there are differences in potency and duration of effect among the novel opioids.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Bianca Maria Casella, James P. P. Farmer, Desislava N. N. Nesheva, Huw E. L. Williams, Steven J. J. Charlton, Nicholas D. D. Holliday, Charles A. A. Laughton, Shailesh N. N. Mistry
Summary: Inhibition of CXCR2 is a potential strategy for the treatment of pulmonary diseases and cancers. This study reports the design and synthesis of fluorescent NAMs that selectively bind to CXCR2, enabling the measurement and evaluation of their pharmacological properties. These NAMs can be used as alternative compounds for targeting these receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Hematology
Foteini-Nafsika Damaskinaki, Natalie J. Jooss, Eleyna M. Martin, Joanne C. Clark, Mark R. Thomas, Natalie S. Poulter, Jonas Emsley, Barrie Kellam, Steve P. Watson, Alexandre Slater
Summary: This study investigates the binding sites of three high-affinity nanobodies, Nb2, Nb21, and Nb35, on the platelet-signaling receptor GPVI. The researchers found that all three nanobodies can bind to the D1 domain of GPVI and inhibit collagen-induced GPVI signaling. They also identified common target residues, Arg46, Tyr47, and Ala57, on GPVI for these nanobodies. Additionally, the study negates the idea that GPVI dimerization induces a conformational change required for ligand binding.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Meeting Abstract
Pharmacology & Pharmacy
James Farmer, Nicholas Holliday, Shailesh Mistry, Charles Laughton
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Abdelfattah Faouzi, Haoqing Wang, Saheem A. Zaidi, Jeffrey F. DiBerto, Tao Che, Qianhui Qu, Michael J. Robertson, Manish K. Madasu, Amal El Daibani, Balazs R. Varga, Tiffany Zhang, Claudia Ruiz, Shan Liu, Jin Xu, Kevin Appourchaux, Samuel T. Slocum, Shainnel O. Eans, Michael D. Cameron, Ream Al-Hasani, Ying Xian Pan, Bryan L. Roth, Jay P. McLaughlin, Georgios Skiniotis, Vsevolod Katritch, Brian K. Kobilka, Susruta Majumdar
Summary: This study presents an approach to design safer analgesics by targeting a conserved sodium ion-binding site in mu-opioid receptor (mu OR) using bitopic fentanyl derivatives. Cryo-electron microscopy structures reveal key interactions between the ligands and mu OR, demonstrating nanomolar potency, high efficacy, and reduced adverse effects. This study suggests the potential of the mu OR sodium ion-binding site as a target for the design of safer analgesics.