Article
Chemistry, Multidisciplinary
Yongjin Xu, Chunxia Gao, Liliana Haversen, Thomas Lundback, Joakim Andreasson, Morten Grotli
Summary: In this study, the synthesis and characterization of a photoswitchable DFG-out kinase inhibitor were reported, and the photocontrol of the target kinase was demonstrated in both enzymatic and living cell assays.
CHEMICAL COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Yongjin Xu, Chunxia Gao, Mans Andreasson, Liliana Haversen, Marta P. Carrasco, Cassandra Fleming, Thomas Lundback, Joakim Andreasson, Morten Grotli
Summary: In this study, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, allowing for photonic control of RET activity. By modifying the molecular structure, the difference in bioactivity between the two isomers was increased. The quinoline-based compound showed the most promising results, exhibiting significant bioactivity difference in both biochemical and cellular assays.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xin Wu, Yuan Zhang, Songbin Liu, Chang Liu, Guotao Tang, Xuan Cao, Xiaoyong Lei, Junmei Peng
Summary: Fragment-based drug discovery is gaining momentum in academia, large pharmaceutical companies, and biotechnology laboratories as a complementary method to traditional screening. It involves selecting favorable combinations of fragments or extending new drug molecules to obtain highly active drug candidates. This article highlights different types and classifications of linkers published in the past decade, explaining how these linkers are designed and introduced into lead compounds to obtain potential candidate compounds.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Lewis D. Turner, Chi H. Trinh, Ryan A. Hubball, Kyle M. Orritt, Chi-Chuan Lin, Julie E. Burns, Margaret A. Knowles, Colin W. G. Fishwick
Summary: This study describes a structure-guided approach to design a selective FGFR2 inhibitor, resulting in a nanomolar potency inhibitor with moderate selectivity for FGFR2. The study reveals that inhibitor-specific morphological differences may play a crucial role in selectivity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Washington A. Pereira, Erica C. M. Nascimento, Joao B. L. Martins
Summary: This study analyzed four main drugs for the treatment of chronic myeloid leukemia and their derivative molecules, focusing on structural effects. Electronic and docking studies revealed structural similarities between different drugs and modifications on new generations of imatinib-based inhibitors.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Multidisciplinary
Pierre Matricon, Duc Duy Vo, Zhan-Guo Gao, Jan Kihlberg, Kenneth A. Jacobson, Jens Carlsson
Summary: Fragment-based drug discovery relies on optimizing weakly binding ligands for affinity and selectivity, with strategies for structure-based evolution of fragments binding to a G protein-coupled receptor resulting in nanomolar ligands with significantly improved binding affinity and subtype selectivity.
CHEMICAL COMMUNICATIONS
(2021)
Article
Computer Science, Information Systems
Zhihui Yang, Juan Liu, Xuekai Zhu, Feng Yang, Qiang Zhang, Hayat Ali Shah
Summary: In this paper, a novel model called FragDPI is proposed for predicting drug-protein binding affinity. Unlike other methods, we encode the sequences based on conserved fragments and unify the protein and drug into a vector. Moreover, a two-step training strategy is adopted, with unsupervised learning to learn fragment interactions and supervised learning to predict binding affinities. Experimental results demonstrate the superiority of FragDPI.
FRONTIERS OF COMPUTER SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Dmitry A. Shulga, Nikita N. Ivanov, Vladimir A. Palyulin
Summary: The article proposes a way to enhance the throughput and availability of the fragment-based drug discovery (FBDD) methods by using an in silico approach to assess the contribution of molecular fragments to ligand-receptor binding energy. The proposed approach has been shown to have a wider applicability domain and can result in similar decisions as those made using experimental methods. The method is also robust to the choice of a scoring function with decent scoring power.
Review
Oncology
Marta Bon, Alan Bilsland, Justin Bower, Kirsten McAulay
Summary: Fragment-based drug discovery (FBDD) is a complementary approach to high-throughput screening (HTS) that involves screening smaller and less complex molecules. This method has shown promise in optimizing hard-to-drug targets, and recent developments have highlighted its utility against previously undruggable targets.
MOLECULAR ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jing Zhou, Yangyang Zhao, Ruizhe Yang, Zhong Zhang, Yan Jin, Lei Wang, Min Huang
Summary: Three candidate drugs (Lapatinib, B001, and C001) with strong binding affinity to Coxsackievirus A16 (CVA16) have been discovered, and they can enter the binding pocket of the virus. These findings provide new ideas and technical guidance for designing and applying therapeutics against CVA16.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Debomita Bhattacharya, Alice Shi Ming Li, Barnali Paul, Uddipta Ghosh Dastidar, Vijayaratnam Santhakumar, Dipika Sarkar, Irene Chau, Fengling Li, Trisha Ghosh, Masoud Vedadi, Arindam Talukdar
Summary: Protein arginine methyltransferases (PRMTs) play a crucial role in the methylation of arginine groups in protein substrates, and dysregulated expression of these enzymes is associated with various diseases. Development of PRMT inhibitors has shown promise as a therapeutic strategy, and small fragment inhibitors have been identified as potential starting points for drug development. In this study, a fragment-based approach was used to discover selective Class I PRMT inhibitors, and lead compounds 55 and 56 displayed potent inhibition of PRMT4. These findings provide new options for the development of potent and selective PRMT4 inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Namdev S. Togre, Ana M. Vargas, Gunapati Bhargavi, Mohan Krishna Mallakuntla, Sangeeta Tiwari
Summary: The emergence of drug-resistant mycobacteria is a global threat that requires the development of new potent anti-mycobacterial drugs. Fragment-based drug discovery (FBDD) has been recognized as a popular approach to identify potent fragment molecules using virtual, computational, and biophysical methods. FBDD overcomes the limitations of traditional methods and is important for combating NTM and Mtb infections.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Youhai Tan, Lingxue Dai, Weifeng Huang, Yinfeng Guo, Shuangjia Zheng, Jinping Lei, Yuedong Yang, Hongming Chen
Summary: In this study, a novel framework called DRlinker was proposed to control fragment linking for generating candidate compounds with specified attributes using reinforcement learning. The method has been proven effective for various tasks, including controlling linker length and log P, optimizing predicted bioactivity of compounds, and handling multiple objectives.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Multidisciplinary
Ankit Kumar Singh, Jurica Novak, Adarsh Kumar, Harshwardhan Singh, Suresh Thareja, Prateek Pathak, Maria Grishina, Amita Verma, Jagat Pal Yadav, Habibullah Khalilullah, Vikas Pathania, Hemraj Nandanwar, Mariusz Jaremko, Abdul-Hamid Emwas, Pradeep Kumar
Summary: In this study, new pyrimidine-sulfonamide hybrid BRAF(V600E) inhibitors were designed and molecular docking and dynamics simulations were performed. These designed compounds have better interactions with the core active site of BRAF(V600E) protein compared to previous inhibitors, potentially providing a solution for BRAF(V600E) resistance and malignancies induced by dimer BRAF mutants.
Article
Chemistry, Medicinal
Youhai Tan, Lingxue Dai, Weifeng Huang, Yinfeng Guo, Shuangjia Zheng, Jinping Lei, Hongming Chen, Yuedong Yang
Summary: A novel framework called DRlinker was proposed in this study to control fragment linking and generate compounds with specified attributes through reinforcement learning. The method has been demonstrated to be effective in various tasks, including controlling linker length and log P, optimizing predicted bioactivity of compounds, and achieving various multiobjective tasks.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
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)