Article
Biochemistry & Molecular Biology
Francesca Ferrari, Maicol Bissaro, Simone Fabbian, Jessica De Almeida Roger, Stefano Mammi, Stefano Moro, Massimo Bellanda, Mattia Sturlese
Summary: Fragment-based lead discovery is an efficient method for developing new drugs. The new computational protocol HT-SuMD allows for automatic screening of thousands of fragments, showing remarkable agreement with NMR-based screening. Virtual screening on a larger library of fragments confirmed all selected hits as Bcl-X-L binders, representing the largest computational fragment screening based on MD to date.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Medicinal
Benjamin Diethelm-Varela
Summary: Targeted therapies are a promising approach to personalized cancer care, with fragment-based drug discovery (FBDD) methods playing a key role in guiding ligand design and providing structural information. Nuclear magnetic resonance spectroscopy is a useful tool in fragment discovery, with its detection capabilities and versatility being valuable in the drug discovery process.
Review
Pharmacology & Pharmacy
Md. Moinul, Samima Khatun, Sk. Abdul Amin, Tarun Jha, Shovanlal Gayen
Summary: This review discusses the application of fragment-based drug design in cancer treatment, as well as the design strategies for different targets, providing insights for finding suitable lead compounds through fragment-based design in high throughput screening.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Felix Torres, Gabriela Stadler, Witek Kwiatkowski, Julien Orts
Summary: Protein-fragment complex structures are important for designing lead molecules. X-ray crystallography is the usual method, but has a high failure rate. NMR is an alternative method for weakly interacting complexes, but protein signal assignment is time-consuming. NMR2 is a rapid method for determining protein-fragment complex structures. The study presents the expected performance of NMR2 and proposes a strategy to improve success rate. NMR2 is confirmed as an alternative to X-ray crystallography for solving protein-fragment complex structures.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Luca G. Mureddu, Geerten W. Vuister
Summary: The definitions of pharmaceutical drug and drug discovery have changed significantly over the past century. Drug discovery now involves multiple stages aimed at obtaining molecules that can interact with specific biomolecular targets. High Throughput Screening (HTS) and Fragment Based Drug Design (FBDD) are commonly used approaches in the early stages of drug discovery. Nuclear Magnetic Resonance (NMR) spectroscopy is widely used in both industry and academia for FBDD. This manuscript discusses the role of NMR in the development of successful and unsuccessful molecules, focusing on the techniques used and evaluating the strengths and weaknesses of each stage through case studies.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Medicinal
Paolo Di Fruscia, Fredrik Edfeldt, Igor Shamovsky, Gavin W. Collie, Anna Aagaard, Louise Barlind, Ulf Borjesson, Eva L. Hansson, Richard J. Lewis, Magnus K. Nilsson, Linda Oster, Josefine Pemberton, Lena Ripa, R. Ian Storer, Helena Kack
Summary: MEK1 kinase plays a critical role in key cellular processes and its dysfunction is strongly linked to several human diseases, particularly cancer. Various small-molecule inhibitors targeting this kinase have been reported, with the majority focusing on an allosteric pocket proximal to the ATP binding site. Four allosteric MEK1 inhibitors have been approved to date, with limited chemotypes structurally shown to bind to this site.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
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
Biochemistry & Molecular Biology
Chen Peng, Andrew T. Namanja, Eva Munoz, Haihong Wu, Thomas E. Frederick, Mitcheell Maestre-Martinez, Isaac Iglesias Fernandez, Qi Sun, Carlos Cobas, Chaohong Sun, Andrew M. Petros
Summary: Fragment-based drug discovery (FBDD) and validation of small molecule binders using NMR spectroscopy is an established and widely used method in the early stages of drug discovery. This article presents the development of software tools for analyzing 2D NMR data for FBDD and hit validation purposes.
JOURNAL OF BIOMOLECULAR NMR
(2023)
Article
Biochemistry & Molecular Biology
Pooja Gupta, Sherine E. Thomas, Shaymaa A. Zaidan, Maria A. Pasillas, James Cory-Wright, Ailidh Burgess, Victor Sebastian-Perez, Emma Cattermole, Clio Meghir, Chris Abell, Anthony G. Coyne, William R. Jacobs, Tom L. Blundell, Sangeeta Tiwari, Vitor Mendes
Summary: The study evaluated the ligandability of four enzymes in the L-arginine biosynthesis pathway of Mycobacterium tuberculosis, identifying hits with potential anti-tuberculosis activity. These results showcase the potential for targeting more enzymes in this pathway in dedicated drug discovery programs.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Beatrice Balboni, Shailesh Kumar Tripathi, Marina Veronesi, Debora Russo, Ilaria Penna, Barbara Giabbai, Tiziano Bandiera, Paola Storici, Stefania Girotto, Andrea Cavalli
Summary: In this study, we identified promising GSK-3 beta inhibitors through 1D F-19 NMR fragment screening and biophysical assays. We also proposed an alternative screening workflow to overcome the limitations of common GSK-3 beta inhibitors and found selective inhibitors and/or inhibitors capable of modulating GSK-3 beta activity without complete inhibition.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Sheikh Mohammed Arif, R. Andres Floto, Tom L. Blundell
Summary: Cystic fibrosis is a progressive genetic disease that predisposes the lungs and other organs to long-lasting microbial infections. Pseudomonas aeruginosa is the most prevalent and deadly pathogen among these microbes. Due to the emergence of drug-resistant strains, there is an urgent need for new antibacterials to treat P. aeruginosa infections. Structure-guided fragment-based drug discovery is a powerful approach in drug development, but it has not been widely used in the development of anti-pseudomonal molecules.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemical Research Methods
Riku Katsuki, Tsubasa Numayama, Yudai Tabuchi, Jaiyam Sharma, Naohito Satake, Adarsh Sandhu, Masumi Taki
Summary: This article presents a fragment-based screening approach to drug discovery using a solvatochromic protein binder as a fluororeporter. The affinity of the lead compound can be observed by the naked eye and quantified using a portable fluorophotometer.
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jared J. Anderson, Michael J. Grillo, Daniel A. Harki
Summary: NF-kappa B inducing kinase (NIK) is crucial for immune responses and its dysregulation is associated with inflammatory diseases and cancers. Researchers have developed a series of allosteric, fragment-sized NIK ligands that bind effectively with micromolar potency.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Julia Revillo Imbernon, Luca Chiesa, Esther Kellenberger
Summary: The fragment approach is an effective method for drug design, especially for challenging therapeutic targets. The key factors for success include the selection of screened chemical library and biophysical screening method, as well as the quality of chosen fragment and structural information for developing a drug-like ligand.
FRONTIERS IN CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Tom Dekker, Mathilde A. C. H. Janssen, Christina Sutherland, Rene W. M. Aben, Hans W. Scheeren, Daniel Blanco-Ania, Floris P. J. T. Rutjes, Maikel Wijtmans, Iwan J. P. de Esch
Summary: The success of fragment-based drug discovery (FBDD) is closely related to library design. A workflow in KNIME software has been created to guide the design of fragment libraries, considering chemical diversity and novelty of the fragments, as well as their three-dimensional (3D) character. This design tool can create large and diverse libraries or select representative compounds to enrich existing libraries.
ACS MEDICINAL CHEMISTRY LETTERS
(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)