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.
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
Pharmacology & Pharmacy
Muhetaer Mukaidaisi, Andrew Vu, Karl Grantham, Alain Tchagang, Yifeng Li
Summary: Fragment-based drug design is an effective method to constrain the search space and better utilize biologically active compounds. This study integrates a graph fragmentation-based deep generative model with deep evolutionary learning for large-scale multi-objective molecular optimization, and applies protein-ligand binding affinity scores and other desired physicochemical properties as objectives. Experimental results show that the proposed method can generate novel molecules with improved property values and binding affinities.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Dmitry A. Shulga, Nikita N. Ivanov, Vladimir A. Palyulin
Summary: The R-FBDD approach aims to estimate the contributions of fragments in a molecule using scoring functions, helping researchers identify binding anchors and guide further drug development effectively.
MENDELEEV COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Justin D. Dietrich, Kenton L. Longenecker, Noel S. Wilson, Christian Goess, Sanjay C. Panchal, Steven L. Swann, Andrew M. Petros, Adrian D. Hobson, David Ihle, Danying Song, Paul Richardson, Kenneth M. Comess, Philip B. Cox, Amanda Dombrowski, Kathy Sarris, Diana L. Donnelly-Roberts, David B. Duignan, Arthur Gomtsyan, Paul Jung, A. Chris Krueger, Suzanne Mathieu, Andrea McClure, Vincent S. Stoll, Jill Wetter, John A. Mankovich, Philip J. Hajduk, Anil Vasudevan, Robert H. Stoffel, Chaohong Sun
Summary: TNFα is a key soluble cytokine involved in systemic inflammation, and development of drugs targeting it has proven challenging. A fragment-based drug discovery approach led to the identification of lead compounds with improved binding efficiency and drug-like properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Mike Buehrmann, Shivakrishna Kallepu, Jonas D. Warmuth, Jan N. Wiese, Christiane Ehrt, Helge Vatheuer, Wolf Hiller, Carina Seitz, Laura Levy, Paul Czodrowski, Sonja Sievers, Matthias P. Mueller, Daniel Rauh
Summary: Based on the computational workflow FRAGTORY, we designed a pharmacophore diversity-driven fragment library to guide synthesis efforts and build a curated library of sp3-enriched fragments. Through protein crystallography and isothermal titration calorimetry, we identified structurally novel ligands, validating the applicability of our experimental approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Chemistry, Medicinal
Daniel R. R. Bryan, John L. L. Kulp Jr, Manoj K. K. Mahapatra, Richard L. L. Bryan, Usha Viswanathan, Micah N. N. Carlisle, Surim Kim, William D. D. Schutte, Kevaughn V. V. Clarke, Tony T. T. Doan, John L. L. Kulp III
Summary: Fragment-based drug design utilizes data on the binding of small chemical fragments to proteins to create new drug molecules. A web application called BMaps has been developed to make this approach widely accessible through simplified user interfaces. BMaps provides access to a large repository of proteins, precomputed fragment maps, druggable hotspots, and water maps, and allows users to use their own structures or those from external databases. This approach combines conventional tools with fragment-based design in an easy-to-use automated web application. Rating: 8/10
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Ross P. Thomas, Rachel E. Heap, Francesca Zappacosta, Emma K. Grant, Peter Pogany, Stephen Besley, David J. Fallon, Michael M. Hann, David House, Nicholas C. O. Tomkinson, Jacob T. Bush
Summary: The study introduces a screening platform that combines 'direct-to-biology' high-throughput chemistry with photoreactive fragments for rapid synthesis and screening of chemical tools. The platform allows for iterative design-make-test cycles to accelerate the development and optimization of chemical tools and medicinal chemistry starting points with minimal resource investment.
Article
Chemistry, Medicinal
Blessy M. Suresh, Amirhossein Taghavi, Jessica L. Childs-Disney, Matthew D. Disney
Summary: Although there are challenges in fragment-based drug discovery (FBDD) for RNA targets, some bioactive ligands have been identified by integrating known methods of RNA binder discovery with fragment-based approaches. This review discusses various fragment-based approaches for RNA targets, providing insights into experimental design and outcomes for future research. Investigations into the molecular recognition of RNA by fragments address important questions such as the limits of molecular weight for selective binding and the physicochemical properties favorable for RNA binding and bioactivity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Meredith J. Zeller, Oleg Favorov, Kelin Li, Ashok Nuthanakanti, Dina Hussein, Aureliane Michaud, Daniel A. Lafontaine, Steven Busan, Alexander Serganov, Jeffrey Aube, Kevin M. Weeks
Summary: In this study, a new technology was developed that utilizes fragment-based screening and RNA structure probing to discover small-molecule fragments that bind to a target RNA structure. Using structure-activity relationship information, a novel ligand was designed with high affinity for diverse RNA targets.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Jonghwan Choi, Sangmin Seo, Seungyeon Choi, Shengmin Piao, Chihyun Park, Sung Jin Ryu, Byung Ju Kim, Sanghyun Park
Summary: We proposed a multi-objective molecular generation method with a novel parsing algorithm for molecular string representation and a modified reinforcement learning method for efficient training. Our model achieved success rates of 84% in GSK3b+JNK3 inhibitor generation and 99% in Bcl-2 family inhibitor generation tasks.
COMPUTERS IN BIOLOGY AND MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Fergus Imrie, Thomas E. Hadfield, Anthony R. Bradley, Charlotte M. Deane
Summary: This study presents a method that improves the performance of generative models by incorporating 3D structural information, allowing for greater control over the design process in molecular design. The method performs well in linker and R-group design, effectively generating molecules with high 3D similarity.
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
Christopher N. Johnson, Daniel A. Erlanson, Christopher W. Murray, David C. Rees
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Chemistry, Medicinal
Richard J. Hall, Christopher W. Murray, Marcel L. Verdonk
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Chemistry, Medicinal
Christopher N. Johnson, Daniel A. Erlanson, Wolfgang Jahnke, Paul N. Mortenson, David C. Rees
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Tom D. Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko M. Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E. H. Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M. Griffiths-Jones, John F. Lyons, Vanessa Martins, Sandra Muench, Joanne M. Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C. Rees, Sharna J. Rich, Caroline Richardson, Harpreet Saini, Neil T. Thompson, Nicola G. Wallis, Hugh Walton, Nicola E. Wilsher, Alison J. -A. Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W. Murray
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Paul N. Mortenson, Daniel A. Erlanson, Iwan J. P. de Esch, Wolfgang Jahnke, Christopher N. Johnson
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Review
Pharmacology & Pharmacy
Marc O'Reilly, Anne Cleasby, Thomas G. Davies, Richard J. Hall, R. Frederick Ludlow, Christopher W. Murray, Dominic Tisi, Harren Jhoti
DRUG DISCOVERY TODAY
(2019)
Article
Chemistry, Medicinal
Tom D. Heightman, James F. Callahan, Elisabetta Chiarparin, Joseph E. Coyle, Charlotte Griffiths-Jones, Ami S. Lakdawala, Rachel McMenamin, Paul N. Mortenson, David Norton, Torren M. Peakman, Sharna J. Rich, Caroline Richardson, William L. Rumsey, Yolanda Sanchez, Gordon Saxty, Henriette M. G. Willems, Lawrence Wolfe, Alison J. -A. Woolford, Zining Wu, Hongxing Yan, Jeffrey K. Kerns, Thomas G. Davis
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Daniel A. Erlanson, Iwan J. P. de Esch, Wolfgang Jahnke, Christopher N. Johnson, Paul N. Mortenson
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Wolfgang Jahnke, Daniel A. Erlanson, Iwan J. P. de Esch, Christopher N. Johnson, Paul N. Mortenson, Yuji Ochi, Tatsuya Urushima
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Joao Morado, Paul N. Mortenson, Marcel L. Verdonk, Richard A. Ward, Jonathan W. Essex, Chris-Kriton Skylaris
Summary: The quality of force field parameterization plays a crucial role in determining the accuracy of observable properties computed from molecular mechanics simulations. ParaMol is a Python package focused on parameterizing bonded and nonbonded terms of druglike molecules by fitting to ab initio data. Through case studies, ParaMol demonstrates the ability to derive near-ideal parameters within the constraints of the functional form, while also discussing best practices and weighting methods for parameterization routes.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Physical
Joao Morado, Paul N. Mortenson, J. Willem M. Nissink, Marcel L. Verdonk, Richard A. Ward, Jonathan W. Essex, Chris-Kriton Skylaris
Summary: Conformational analysis is crucial in drug design, and molecular mechanics simulation methods are used to generate ensembles of structures to provide reliable structural information. Reparameterizing the force field can generate FFs that closely reproduce QM results, and the MC acceptance rate is strongly correlated with various phase space overlap measurements, serving as a robust metric to evaluate the similarity between MM and QM levels of theory.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Medicinal
Joao Morado, Paul N. Mortenson, J. Willem M. Nissink, Jonathan W. Essex, Chris-Kriton Skylaris
Summary: We present a comparative study on the performance of different molecular models in simulating the stability and properties of 10 gamma-fluorohydrins. The results show that the ANI-2x model tends to predict stronger hydrogen bonding and overstabilize global minima, while conventional force fields still play an important role in condensed-phase simulations. This study provides guidelines for the future development and application of force fields and machine learning potentials.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Jeffrey D. St Denis, Gianni Chessari, Anne Cleasby, Benjamin D. Cons, Suzanna Cowan, Samuel E. Dalton, Charlotte East, Christopher W. Murray, Marc O'Reilly, Torren Peakman, Magdalini Rapti, Jessie L. Stow
Summary: Fragment-based drug discovery is an established method for finding efficient starting points in drug discovery programs. Electrophilic fragment screening has gained attention for identifying covalent hits against challenging drug targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Gianni Chessari, Rachel Grainger, Rhian S. Holvey, R. Frederick Ludlow, Paul N. Mortenson, David C. Rees
Summary: This study analyzed 131 fragment-to-lead examples targeting various protein families between 2015-2019, identifying the most common polar functional groups involved in fragment-protein binding and highlighting the key role of growth from carbocentric vectors. The results suggest that robust C-H functionalisation methods that tolerate the polar functionality on fragments could be transformative for fragment-based drug discovery.
Review
Biochemistry & Molecular Biology
Jeffrey D. St Denis, Richard J. Hall, Christopher W. Murray, Tom D. Heightman, David C. Rees
Summary: This review discusses the growing demand for organic synthesis in facilitating fragment-based drug discovery, particularly focusing on polar unprotected fragments. It highlights the challenge of synthesis that slows down drug discovery process, and some fragments cannot be further optimized due to synthetic difficulties.
RSC MEDICINAL CHEMISTRY
(2021)