Article
Chemistry, Medicinal
Tuan Xu, Shuaizhang Li, Andrew J. Li, Jinghua Zhao, Srilatha Sakamuru, Wenwei Huang, Menghang Xia, Ruili Huang
Summary: In this study, machine learning models were developed to predict novel AChE and BChE inhibitors. The models showed good performance in virtual screening and increased the hit rate of assay. A total of 88 novel AChE and 126 novel BChE inhibitors were identified, with significant inhibitory effects. Structure-activity relationship analysis revealed scaffolds for chemistry design and optimization.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Michele Rossi, Michela Freschi, Luciana de Camargo Nascente, Alessandra Salerno, Sarah de Melo Viana Teixeira, Florian Nachon, Fabien Chantegreil, Ondrej Soukup, Lukas Prchal, Marco Malaguti, Christian Bergamini, Manuela Bartolini, Cristina Angeloni, Silvana Hrelia, Luiz Antonio Soares Romeiro, Maria Laura Bolognesi
Summary: Alzheimer's disease's multifactorial nature hinders effective drug development. A research team developed sustainable multi-target-directed ligands based on inexpensive cashew nutshell liquid, selecting compounds through cell toxicity and enzymatic studies to confirm their activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Benoit David, Pascal Schneider, Philipp Schaefer, Joerg Pietruszka, Holger Gohlke
Summary: In this study, virtual screening approaches were used to search for potent AChE inhibitors in databases. A compound with promising inhibitory activity, S-I 26, was identified and has the potential to be developed as a therapeutic drug.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Ginson George, Vishal Payyalot Koyiparambath, Sunitha Sukumaran, Aathira Sujathan Nair, Leena K. Pappachan, Abdullah G. Al-Sehemi, Hoon Kim, Bijo Mathew
Summary: This review highlights the recent evidence of chalcones as a privileged structure in the development of drugs for Alzheimer's disease. Different classes of chalcone-derived analogs and the importance of certain functionalities in exhibiting pharmaceutical activity are summarized.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Paptawan Suwanhom, Jirakrit Saetang, Pasarat Khongkow, Teerapat Nualnoi, Varomyalin Tipmanee, Luelak Lomlim
Summary: A quinoxaline scaffold showed various bioactivities in pharmacotherapeutic interests. In this study, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors, showing potent inhibitory activities against AChE and BChE, preferring to bind with PAS site.
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)
Review
Biochemistry & Molecular Biology
Jared A. Miles, Benjamin P. Ross
Summary: Virtual screening techniques, such as LBVS and SBVS, have emerged as powerful tools for drug discovery in Alzheimer’s disease (AD). Cholinesterases, well-suited for virtual screening, have been the target of numerous studies utilizing these techniques to discover novel inhibitors. Confirmation of the in vitro activity of screening compounds is highlighted as a crucial step in the drug discovery process.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Chengqian Wei, Junjie Huang, Yu Wang, Yifang Chen, Xin Luo, Shaobo Wang, Zengxue Wu, Jixiang Chen
Summary: A series of new oxadiazole sulfone derivatives containing an amide moiety were synthesized to screen high-efficiency antibacterial agents for rice bacterial diseases. Compound 10 showed excellent antibacterial activity against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola, with EC50 values superior to commercial bactericides. Compound 10 demonstrated superior protective and curative activities against rice bacterial leaf blight and rice bacterial leaf streak compared to other tested compounds. Additionally, compound 10 exhibited potential mechanisms of action by affecting extracellular polysaccharides, cell membranes, and enzyme activity of dihydrolipoamide S-succinyltransferase to inhibit the growth of Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Mohd Imran Khan, Park Taehwan, Yunseong Cho, Marcus Scotti, Renata Priscila Barros de Menezes, Fohad Mabood Husain, Suliman Yousef Alomar, Mohammad Hassan Baig, Jae-June Dong
Summary: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting a large population worldwide. This study used machine learning modeling to search for potential drug candidates that inhibit acetylcholinesterase, providing a new approach for the treatment of AD.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Dongyan Gu, Mengmeng Zhang, Lvtao Cai, Chang Wang, Yu -Bo Zhou, Jia Li, Rong Sheng
Summary: Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a hit for inhibiting PI3K alpha activity through virtual screening. Structural modifications based on similarity search and molecular docking yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited improved PI3K alpha inhibitory activity with good isoform selectivity and demonstrated promising pharmacokinetic properties. Further development of compound 49b as a potential PI3Ka inhibitor is warranted.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dawid Panek, Anna Pasieka, Gniewomir Latacz, Paula Zareba, Michal Szczech, Justyna Godyn, Fabien Chantegreil, Florian Nachon, Xavier Brazzolotto, Anna Skrzypczak-Wiercioch, Maria Walczak, Magdalena Smolik, Kinga Salat, Georg Hoefner, Klaus Wanner, Anna Wieckowska, Barbara Malawska
Summary: A highly selective hBuChE inhibitor (29) with potential benefits for treating Alzheimer's disease has been identified through extensive in vitro and in vivo evaluations.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Chemistry, Medicinal
Raquel B. M. de Almeida, Deyse B. B. Barbosa, Mayra R. R. do Bomfim, Jessika A. O. Amparo, Bruno S. S. Andrade, Silvia L. L. Costa, Joaquin M. Campos, Jorddy N. Cruz, Cleydson B. R. Santos, Franco H. A. Leite, Mariana B. B. Botura
Summary: The compound ZINC390718 was found to exhibit inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and showed low cytotoxicity in vitro. Molecular dynamics (MD) simulation revealed that ZINC390718 interacted with the catalytic residue sites of both enzymes. These findings suggest that ZINC390718 could be a potential chemotype for the development of new dual cholinesterase inhibitors.
Article
Automation & Control Systems
Yue Zhao, Rui-fang Chen, Zhen-Ke Deng, Liu-Xia Zhang, Yan Cheng, Alex F. Chen, Dong-Sheng Cao
Summary: RSK2 plays a critical role in cell proliferation and anticancer therapy as a potential target. Virtual screening identified compounds with potential anticancer activity.
CHEMOMETRICS AND INTELLIGENT LABORATORY SYSTEMS
(2021)
Article
Biochemistry & Molecular Biology
Fazal Rahim, Hayat Ullah, Muhammad Taha, Rafaqat Hussain, Maliha Sarfraz, Rashid Iqbal, Naveed Iqbal, Shoaib Khan, Syed Adnan Ali Shah, Marzough Aziz Albalawi, Mahmoud A. Abdelaziz, Fatema Suliman Alatawi, Abdulrahman Alasmari, Mohamed I. Sakran, Nahla Zidan, Ibrahim Jafri, Khalid Mohammed Khan
Summary: Triazole-based thiosemicarbazone derivatives were synthesized and characterized by spectroscopic techniques. Two derivatives, 6i and 6b, showed strong inhibitory effects on acetylcholinesterase and butyrylcholinesterase enzymes. Molecular docking studies revealed their binding interactions with the active sites of the targeted enzymes.
Article
Biochemistry & Molecular Biology
Qi Li, Jun Mo, Baichen Xiong, Qinghong Liao, Ying Chen, Yuanyuan Wang, Shuaishuai Xing, Siyu He, Weiping Lyu, Ning Zhang, Haopeng Sun
Summary: S05014 is identified as a highly effective tyrosinase inhibitor with good medication safety, showing inhibitory effects on melanogenesis. It has the potential to be used in anti-Parkinsonian syndrome due to its ability to decrease tyrosinase function and expression.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Xianglin Chu, Siyu He, Yang Liu, Yijun Liu, Feng Feng, Qinglong Guo, Li Zhao, Haopeng Sun
Summary: This article provides an overview of the physiological and pathological functions of human aldo-keto reductase family 1C1 (AKR1C1) and its relationship with diseases. It also summarizes the development of AKR1C1 inhibitors and the interaction between inhibitors and AKR1C1. Furthermore, it discusses the design ideals of selective AKR1C1 inhibitors and the prospects of AKR1C1 in disease treatment.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Review
Biochemistry & Molecular Biology
Yuanyuan Wang, Baichen Xiong, Shuaishuai Xing, Ying Chen, Qinghong Liao, Jun Mo, Yao Chen, Qi Li, Haopeng Sun
Summary: Tyrosinase is a bifunctional enzyme involved in melanogenesis. It is targeted for various applications such as skin whitening, anticancer treatment, antibacterial properties, and fruit and vegetable preservation. Medicinal chemists have developed diverse tyrosinase inhibitors with novel scaffolds and synergistic effects to regulate multiple targets. This review covers natural and synthetic tyrosinase inhibitors with potential applications in various fields.
CURRENT MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Qi Li, Baichen Xiong, Yuanyuan Wang, Weiping Lyu, Shuaishuai Xing, Ying Chen, Qinghong Liao, Siyu He, Feng Feng, Wenyuan Liu, Yao Chen, Haopeng Sun
Summary: In this study, two potential candidates for treating neurodegenerative diseases, especially Alzheimer's disease, were selected and optimized based on their inhibitory activity and drug-like properties. These compounds exhibited significant inhibitory capacity and neuroprotective properties, and could potentially improve symptoms and nutritional status of AD patients. The findings provide important insights for the development of new drugs for AD.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xuemei Wei, Guoqi Yu, Hualiang Shen, Yanjuan Luo, Tianbo Shang, Runpu Shen, Meiyang Xi, Haopeng Sun
Summary: Phosphodiesterase 4 (PDE4), highly expressed in mammalian brain, selectively hydrolyzes cAMP, a key regulator of brain functions such as learning and memory. Inhibiting PDE4 can improve cognitive deficits, but its clinical development is hindered by adverse effects. Research on PDE4 subtypes and the development of subtype-specific inhibitors show promise for improved therapeutic benefits and safety.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Yang Liu, Yuting Chen, Jiheng Jiang, Xianglin Chu, Qinglong Guo, Li Zhao, Feng Feng, Wenyuan Liu, Xiaolong Zhang, Siyu He, Peng Yang, Pengfei Fang, Haopeng Sun
Summary: AKR1C3 is overexpressed in hormone-related cancers and is correlated with tumor development and aggressiveness. A new class of AKR1C3 inhibitors with potent inhibitory activity and selectivity for closely related isoforms has been developed. Co-administration of these inhibitors with doxorubicin can significantly reverse drug resistance in breast cancer cells. These AKR1C3 inhibitors may serve as effective adjuvants to overcome drug resistance in breast cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Chemistry, Multidisciplinary
Xianqing Deng, Haopeng Sun, Bahaa G. M. Youssif
FRONTIERS IN CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Hualiang Shen, Xinde Xu, Yalong Bai, Xiaoping Wang, Yibin Wu, Jia Zhong, Qiyi Wu, Yanjuan Luo, Tianbo Shang, Runpu Shen, Meiyang Xi, Haopeng Sun
Summary: The Kynurenine pathway (KP) is the primary pathway of L-tryptophan metabolism in mammals, and it produces neuroactive metabolites such as kynurenic acid (KA) and quinolinic acid (QA). Imbalance in KP has been associated with aging and neurodegenerative diseases (NDs), leading to the interest in targeting KP enzymes and metabolite-associated receptors, particularly kynurenine monooxygenase (KMO). Although several agents have shown significant improvement in animal models, only one aryl hydrocarbon receptor (AHR) agonist 30 (laquinimod) has entered clinical trials for treating Huntington's disease (HD). This review provides an overview of neuroactive KP metabolites, discusses KP dysregulation in aging and NDs, and summarizes the development of KP regulators in preclinical and clinical studies, offering insights into the potential of targeting KP for NDs treatment in the future.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xu Tang, Shuaishuai Xing, Mingkang Ma, Ziwei Xu, Qianwen Guan, Yuting Chen, Feng Feng, Wenyuan Liu, Tingkai Chen, Yao Chen, Haopeng Sun
Summary: Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which is the most common genetic risk factor for PD. This publication provides a comprehensive overview of the structure, function, and mutations of LRRK2, as well as recent advances and challenges in developing LRRK2 inhibitors. The binding mechanisms, structure-activity relationships, and pharmacokinetic features of inhibitors are emphasized to guide the rational design of LRRK2 inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lu Lu, Jingyi Chen, Wenxiang Tao, Zhimei Wang, Dan Liu, Jiahui Zhou, Xiaoxing Wu, Haopeng Sun, Wei Li, Genzoh Tanabe, Osamu Muraoka, Bo Zhao, Liang Wu, Weijia Xie
Summary: We attempted double-spot structural modification on a side-chain moiety of sulfonium-type alpha-glucosidase inhibitors isolated from Salacia genus. We designed and synthesized a series of sulfonium salts with benzylidene acetal linkage at the C3 ' and C5 ' positions. In vitro enzyme inhibition evaluation showed that compounds with a strong electron-withdrawing group attached at the ortho position on the phenyl ring have stronger inhibitory activities. Notably, the most potent inhibitor 21b showed excellent hypoglycemic effects in mice, comparable to acarbose. Molecular docking of 21b revealed the importance of the newly introduced benzylidene acetal moiety in anchoring the molecule in the enzyme's concave pocket. The identification of 21b as a lead compound may enable structure modification and diversification of sulfonium-type alpha-glucosidase inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Haojie Dong, Xiuquan Ye, Yasheng Zhu, Hao Shen, Hongtao Shen, Weijiao Chen, Minghui Ji, Mingming Zheng, Keren Wang, Zeyu Cai, Haopeng Sun, Yibei Xiao, Peng Yang
Summary: In this study, a series of Osimertinib derivatives were designed as fourth-generation inhibitors targeting Osimertinib-resistant NSCLC. The top candidate D51 showed potent inhibition against EGFR mutants, selectivity against wild-type forms, and favorable in vivo druggability.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Weimin Qiu, Hui Liu, Yijun Liu, Xin Lu, Lei Wang, Yanyu Hu, Feng Feng, Qi Li, Haopeng Sun
Summary: Alzheimer's disease (AD) is a difficult to treat progressive neurodegenerative disease characterized by the accumulation of amyloid beta (A beta) plaques in the brain. A beta interacts with various receptors on the plasma membrane and mediates signaling pathways that contribute to the development of AD. Despite ongoing research, there are currently no effective medications for AD. This review discusses the importance of A beta in the pathogenesis of AD, recent progress in targeting A beta-related receptors and compounds, and the challenges and opportunities in developing effective therapies for AD.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Chang Liu, Manxing Zou, Jianguo Zuo, Huanfang Xie, Weiping Lyu, Jian Xu, Feng Feng, Haopeng Sun, Wenyuan Liu, Xueyang Jiang
Summary: The FDA has approved donepezil, a selective AChE inhibitor, as a first-line drug for mild to moderate AD, but patients taking donepezil often experience peripheral side effects. This study introduces a series of novel thiazole salt AChE inhibitors with nanomolar inhibitory effect on human AChE. Thiamine disulfide prodrugs based on these inhibitors are developed and shown to be converted into thiazole salt AChE inhibitors in the brain, with high brain exposure and stronger inhibitory effects compared to intestinal AChE in vivo. This study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Siyu He, Xianglin Chu, Yujia Wu, Jiheng Jiang, Pengfei Fang, Yuting Chen, Yang Liu, Zhixia Qiu, Yibei Xiao, Zhiyu Li, Di Pan, Qian Zhang, Huanfang Xie, Shuaishuai Xing, Feng Feng, Wenyuan Liu, Qinglong Guo, Li Zhao, Peng Yang, Haopeng Sun
Summary: Aldo-keto reductase 1C3 (AKR1C3) has been found to be associated with tumor development and chemotherapy resistance. Inhibition of AKR1C3 activity can restore the chemosensitivity in ANT-resistant cancers. Biaryl-containing AKR1C3 inhibitors, particularly S07-1066, selectively block AKR1C3-mediated reduction and significantly enhance the cytotoxicity of doxorubicin (DOX) in MCF-7 cells overexpressing AKR1C3. The synergistic effect of S07-1066 and DOX has been demonstrated in vitro and in vivo, suggesting that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xu Tang, Shuaishuai Xing, Mingkang Ma, Ziwei Xu, Qianwen Guan, Yuting Chen, Feng Feng, Wenyuan Liu, Tingkai Chen, Yao Chen, Haopeng Sun
Summary: Parkinson's disease is a neurodegenerative disorder that affects millions of people worldwide. Mutations in the LRRK2 gene are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in both idiopathic and familial PD cases. LRRK2 mutations are involved in various PD pathogeneses, including dysregulation of mitochondrial homeostasis and ciliogenesis.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)