Review
Chemistry, Medicinal
Mohan Krishna Mallakuntla, Namdev S. Togre, Destiny B. Santos, Sangeeta Tiwari
Summary: Tuberculosis (TB) and HIV continue to be global health problems, demanding the development of new drugs for their treatment. Traditional approaches have limitations in producing diverse drugs, necessitating the use of new technologies. Fragment-based drug discovery has proven successful in developing potent inhibitors for various targets.
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)
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
Hai Ping Shao, Tian Hua Wang, Hong Lin Zhai, Ke Xin Bi, Bing Qiang Zhao
Summary: In this study, the interaction mechanisms of two representative peptide inhibitors (11a and PF-07321332) with SARS-CoV-2 main protease (Mpro) were investigated for the first time using molecular dynamics simulation. Fragment-based drug design method was then employed to select fragments from existing SARS-CoV and SARS-CoV-2 inhibitors to replace the original P2 and P3 fragments, resulting in new molecules. Molecular docking, molecular dynamics simulation, and ADMET properties prediction confirmed the excellent activity and physicochemical properties of two molecules (O-74 and N-98), suggesting their potential as new inhibitors for SARS-CoV-2 main protease.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
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
Biochemistry & Molecular Biology
Roberto Leon, Jorge Soto-Delgado, Elizabeth Montero, Matias Vargas
Summary: The study utilizes a fragment-based drug design strategy and heuristic search algorithm to design new inhibitors by deconstructing known ligands and reassembling fragments to generate new ligands. Evaluation of the approaches involves comparing the binding energy of the new ligands with the known ligands.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Cassandra Kennedy, Katherine McPhie, Katrin Rittinger
Summary: The ubiquitin system offers a wealth of potential drug targets, but there is a lack of effective inhibitors for the proteins within this system. Fragment-based drug discovery (FBDD) provides a screening platform that combines structural biology and proteomics to discover inhibitors within the ubiquitin system. This mini review summarizes the current scope and new frontiers of FBDD in relation to ubiquitin-activating, ubiquitin-conjugating, ubiquitin ligase, and deubiquitinating enzymes.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Chemistry, Medicinal
Kasper P. Lundquist, Vipul Panchal, Charlotte H. Gotfredsen, Ruth Brenk, Mads H. Clausen
Summary: The rapid development in fragment-based drug discovery and medicinal targeting of RNA has opened up possibilities for combining technologies and methods in novel ways. This review discusses the use of fragment-based screening against RNA targets, including the latest screening and hit validation methods, and provides insights on future perspectives in this field.
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)
Review
Biochemistry & Molecular Biology
Murtala A. Ejalonibu, Segun A. Ogundare, Ahmed A. Elrashedy, Morufat A. Ejalonibu, Monsurat M. Lawal, Ndumiso N. Mhlongo, Hezekiel M. Kumalo
Summary: Developing new antibiotics targeting resistant Mycobacterium tuberculosis is an appealing strategy to combat the global tuberculosis epidemic, with computational techniques playing a key role in drug design and discovery. Recent advancements in technology have enhanced the chances of drug development, offering hope in the fight against tuberculosis resistance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
Chemistry, Multidisciplinary
Sergio Celis, Fruzsina Hobor, Thomas James, Gail J. Bartlett, Amaurys A. Ibarra, Deborah K. Shoemark, Zsofia Hegedus, Kristina Hetherington, Derek N. Woolfson, Richard B. Sessions, Thomas A. Edwards, David M. Andrews, Adam Nelson, Andrew J. Wilson
Summary: The study presents a general approach to discover orthosteric PPI inhibitors that mimic specific secondary protein structures, validated through experimental examples. Low μM activity selective PPI inhibitors were discovered for two unrelated PPIs, with defined structure-activity relationships established through hit expansion. The approach is believed to have the potential to enable the discovery of inhibitors for a wide range of unrelated secondary structure-mediated PPIs.
Review
Pharmacology & Pharmacy
Agnieszka A. Kaczor, Agata Zieba, Dariusz Matosiuk
Summary: The significance of water molecules in drug design and the use of computational methods. The importance of water molecules in structure-based drug design is discussed, along with computational approaches used to predict solvent-related effects. The WaterMap concept and its application in virtual screening are introduced.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Review
Pharmacology & Pharmacy
Hanna F. Klein, David J. Hamilton, Iwan J. P. de Esch, Maikel Wijtmans, Peter O'Brien
Summary: This review discusses the synthetic strategies for preparing 3D fragments based on 25 papers published from 2011 to mid-May 2020, emphasizing diversity-oriented synthesis, scaffold synthesis and diversification, as well as computational design and synthesis. The conclusion suggests that a workflow combining computational design and other strategies, along with considerations of fragment properties and 3D shape, could promote the wider use of 3D fragments in fragment libraries and facilitate fragment-to-lead optimization.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemical Research Methods
Jerica Wilson, Bahrad A. Sokhansanj, Wei Chuen Chong, Rohan Chandraghatgi, Gail L. Rosen, Hai-Feng Ji
Summary: Fragment-based drug design is a computer-aided drug discovery method, however, it has limitations in processing time and success rate. In this study, a new method called Fragment Databases from Screened Ligands Drug Design (FDSL-DD) was proposed, which intelligently incorporates fragment characteristics into the drug design process to improve the binding affinity between drugs and protein targets.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2024)
Article
Biochemistry & Molecular Biology
Yuri N. Chirgadze, Eugenia A. Boshkova, Kevin P. Battaile, Vitor G. Mendes, Robert Lam, Tiffany S. Y. Chan, Vladimir Romanov, Emil F. Pai, Nickolay Y. Chirgadze
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2018)
Article
Multidisciplinary Sciences
Sangeeta Tiwari, Andries J. van Tonder, Catherine Vilcheze, Vitor Mendes, Sherine E. Thomas, Adel Malek, Bing Chen, Mei Chen, John Kim, Tom L. Blundell, Julian Parkhill, Brian Weinrick, Michael Berney, William R. Jacobs
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Chemistry, Medicinal
Andrew J. Whitehouse, Sherine E. Thomas, Karen P. Brown, Alexander Fanourakis, Daniel S. -H. Chan, M. Daben J. Libardo, Vitor Mendes, Helena I. M. Boshoff, R. Andres Floto, Chris Abell, Tom L. Blundell, Anthony G. Coyne
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Multidisciplinary Sciences
Sherine E. Thomas, Patrick Collins, Rory Hennell James, Vitor Mendes, Sitthivut Charoensutthivarakul, Chris Radoux, Chris Abell, Anthony G. Coyne, R. Andres Floto, Frank von Delft, Tom L. Blundell
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES
(2019)
Article
Biochemistry & Molecular Biology
Daniel Shiu-Hin Chan, Jeannine Hess, Elen Shaw, Christina Spry, Robert Starley, Claudio Dagostin, Marcio V. B. Dias, Ramesh Kale, Vitor Mendes, Tom L. Blundell, Anthony G. Coyne, Chris Abell
BIOCHEMICAL JOURNAL
(2019)
Article
Microbiology
Vitor Mendes, Marta Acebron-Garcia-de-Eulate, Nupur Verma, Michal Blaszczyk, Marcio V. B. Dias, Tom L. Blundell
Article
Chemistry, Medicinal
Mohamad Sabbah, Vitor Mendes, Robert G. Vistal, David M. G. Dias, Monika Zahorszka, Katarina Mikusova, Jana Kordulakova, Anthony G. Coyne, Tom L. Blundell, Chris Abell
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Correction
Chemistry, Medicinal
Mohamad Sabbah, Vitor Mendes, Robert G. Vistal, David M. G. Dias, Monika Zahorszka, Katarina Mikusova, Jana Kordulakova, Anthony G. Coyne, Tom L. Blundell, Chris Abell
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Sherine E. Thomas, Andrew J. Whitehouse, Karen Brown, Sophie Burbaud, Juan M. Belardinelli, Jasper Sangen, Ramanuj Lahiri, Mark Daben J. Libardo, Pooja Gupta, Sony Malhotra, Helena I. M. Boshoff, Mary Jackson, Chris Abell, Anthony G. Coyne, Tom L. Blundell, Rodrigo Andres Floto, Vitor Mendes
NUCLEIC ACIDS RESEARCH
(2020)
Article
Multidisciplinary Sciences
Vitor Mendes, Simon R. Green, Joanna C. Evans, Jeannine Hess, Michal Blaszczyk, Christina Spry, Owain Bryant, James Cory-Wright, Daniel S-H Chan, Pedro H. M. Torres, Zhe Wang, Navid Nahiyaan, Sandra O'Neill, Sebastian Damerow, John Post, Tracy Bayliss, Sasha L. Lynch, Anthony G. Coyne, Peter C. Ray, Chris Abell, Kyu Y. Rhee, Helena I. M. Boshoff, Clifton E. Barry, Valerie Mizrahi, Paul G. Wyatt, Tom L. Blundell
Summary: Coenzyme A (CoA) is a crucial factor in various metabolic pathways and cellular processes, particularly in prokaryotes such as Mycobacterium tuberculosis. The biosynthesis of CoA involves five steps, with the second and third steps catalyzed by a bifunctional protein CoaBC in most prokaryotes. The researchers identified inhibitors of M. tuberculosis CoaB through a high-throughput screen and discovered a cryptic allosteric binding site within the enzyme.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Joanna C. Evans, Dinakaran Murugesan, John M. Post, Vitor Mendes, Zhe Wang, Navid Nahiyaan, Sasha L. Lynch, Stephen Thompson, Simon R. Green, Peter C. Ray, Jeannine Hess, Christina Spry, Anthony G. Coyne, Chris Abell, Helena I. M. Boshoff, Paul G. Wyatt, Kyu Y. Rhee, Tom L. Blundell, Clifton E. I. I. I. I. I. I. Barry, Valerie Mizrahi
Summary: Coenzyme A (CoA) is an essential cofactor in all living cells, and the pathway to CoA biosynthesis is considered a potential source of novel tuberculosis drug targets. This study identified a small molecule inhibitor, compound 1f, that displays on-target activity against Mtb CoaBC, confirming the druggability of this target. Metabolomic profiling following exposure to compound 1f in wild-type Mtb H37Rv produced a signature consistent with perturbations in pantothenate and CoA biosynthesis.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Marta Acebron-Garcia-de-Eulate, Joan Mayol-Llinas, Matthew T. O. Holland, So Yeon Kim, Karen P. Brown, Chiara Marchetti, Jeannine Hess, Ornella Di Pietro, Vitor Mendes, Chris Abell, R. Andres Floto, Anthony G. Coyne, Tom L. Blundell
Summary: This study utilized a fragment-based drug discovery approach to target the MurB protein in Pseudomonas aeruginosa. The findings revealed that a phenylpyrazole scaffold binds to MurB, and through structure optimization, a small molecule with higher affinity was obtained.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Sitthivut Charoensutthivarakul, Sherine E. Thomas, Amy Curran, Karen P. Brown, Juan M. Belardinelli, Andrew J. Whitehouse, Marta Acebron-Garcia-de-Eulate, Jaspar Sangan, Subramanian G. Gramani, Mary Jackson, Vitor Mendes, R. Andres Floto, Tom L. Blundell, Anthony G. Coyne, Chris Abell
Summary: This study identified SAICAR synthetase as a promising target for novel antibiotics against Mycobacterium abscessus. A series of compounds with potent inhibitory activity were developed through fragment library screening and crystallographic screening, providing potential for drug development against Mab.
ACS INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Sherine E. Thomas, William J. McCarthy, Jamal El Bakali, Karen P. Brown, So Yeon Kim, Michal Blaszczyk, Vitor Mendes, Chris Abell, R. Andres Floto, Anthony G. Coyne, Tom L. Blundell
Summary: Antimicrobial resistance is a serious global healthcare concern. This study identifies the non-tuberculous mycobacterium M. abscessus phosphopantetheine adenylyl transferase (PPAT) as a potential target for the development of new antibiotics. The researchers provide structural insights and identify early-stage lead molecules, demonstrating the ligandability of M. abscessus PPAT as an antibiotic target.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
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
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)