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, Medicinal
Marcel Dammann, Jason Stahlecker, Markus O. Zimmermann, Theresa Klett, Kilian Rotzinger, Markus Kramer, Murray Coles, Thilo Stehle, Frank M. Boeckler
Summary: This study presents the design of a Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in early stages of drug discovery. The researchers screened and verified high-affinity binding fragments against a human kinase, and discovered unexplored binding modes and the presence of halogen bonds in these fragments. The study also highlights the benefits and applicability of halogen bonds in early lead development through structure-affinity relationship analysis.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Marcel Dammann, Jason Stahlecker, Markus O. Zimmermann, Theresa Klett, Kilian Rotzinger, Markus Kramer, Murray Coles, Thilo Stehle, Frank M. Boeckler
Summary: We developed a Halogen-Enriched Fragment Library (HEFLib) to study the potential of halogen bonds during the early stages of drug discovery. Our results showed that fragments, with their smaller sizes, are more likely than highly decorated molecules to rely on halogen bonding as a binding mode, providing opportunities for unexplored binding modes. We screened the HEFLib against the human kinase DYRK1a and identified micromolar binding fragments using isothermal titration calorimetry (ITC). The crystal structure of one fragment revealed a noncanonical binding mode, occupying a secondary binding site. Both binding modes featured a halogen bond, which we further evaluated through ab initio calculations. Our study demonstrated that halogen bonds can improve the affinity of fragments and offer promise for early lead development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Federico Riu, Alessandro Ruda, Olof Engstrom, Claudio Muheim, Hani Mobarak, Jonas Stahle, Paul Kosma, Antonio Carta, Daniel O. Daley, Goran Widmalm
Summary: In this study, docking and molecular dynamics simulations were used to identify potential compounds from libraries A and B that can bind to WaaG. The substructure of the inner core of LPS was also investigated. The findings provide insights into the function and catalytic cycle of the enzyme WaaG.
Article
Chemistry, Multidisciplinary
Francois-Xavier Cantrelle, Emmanuelle Boll, Lucile Brier, Danai Moschidi, Sandrine Belouzard, Valerie Landry, Florence Leroux, Frederique Dewitte, Isabelle Landrieu, Jean Dubuisson, Benoit Deprez, Julie Charton, Xavier Hanoulle
Summary: The study utilized NMR spectroscopy to analyze the conformation of the main protease (3CLp) of SARS-CoV-2 and conducted fragment-based screening to identify inhibitors. This research sheds light on the development of potent 3CLp inhibitors.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Chiara Brullo, Federica Rapetti, Sara Abbate, Tommaso Prosdocimi, Archimede Torretta, Marta Semrau, Matteo Massa, Silvana Alfei, Paola Storici, Emilio Parisini, Olga Bruno
Summary: Memory and cognitive functions rely on the levels of cyclic adenosine monophosphate (cAMP) in the brain, which are regulated by the phosphodiesterase 4 (PDE4) enzyme family. Certain PDE4 inhibitors can increase hippocampal cAMP levels, leading to cognitive benefits. Studies have shown that ligands can adopt different conformations, affecting their interaction with the enzyme.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Biancamaria Farina, Luciano Pirone, Gianluca D'Abrosca, Maria Della Valle, Luigi Russo, Carla Isernia, Marica Sassano, Annarita Del Gatto, Sonia Di Gaetano, Laura Zaccaro, Gaetano Malgieri, Emilia M. Pedone, Roberto Fattorusso
Summary: The study identifies PED as a potential pharmacological target for improving insulin sensitivity and glucose tolerance in type II diabetes. By screening PED ligands and studying the PED/PLD1 interaction, the researchers provide valuable information on structural determinants and suggest BPH03 as a promising scaffold for developing novel compounds for therapeutic applications.
ACS CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Hannes Berg, Maria A. Wirtz Martin, Nadide Altincekic, Islam Alshamleh, Jasleen Kaur Bains, Julius Blechar, Betul Ceylan, Vanessa de Jesus, Karthikeyan Dhamotharan, Christin Fuks, Santosh L. Gande, Bruno Hargittay, Katharina F. Hohmann, Marie T. Hutchison, Sophie Marianne Korn, Robin Krishnathas, Felicitas Kutz, Verena Linhard, Tobias Matzel, Nathalie Meiser, Anna Niesteruk, Dennis J. Pyper, Linda Schulte, Sven Trucks, Kamal Azzaoui, Marcel J. J. Blommers, Yojana Gadiya, Reagon Karki, Andrea Zaliani, Philip Gribbon, Marcius da Silva Almeida, Cristiane Dinis Anobom, Anna L. Bula, Matthias Butikofer, Icaro Putinhon Caruso, Isabella Caterina Felli, Andrea T. Da Poian, Gisele Cardoso de Amorim, Nikolaos K. Fourkiotis, Angelo Gallo, Dhiman Ghosh, Francisco Gomes-Neto, Oksana Gorbatyuk, Bing Hao, Vilius Kurauskas, Lauriane Lecoq, Yunfeng Li, Nathane Cunha Mebus-Antunes, Miguel Mompean, Thais Cristtina Neves-Martins, Marti Ninot-Pedrosa, Anderson S. Pinheiro, Letizia Pontoriero, Yulia Pustovalova, Roland Riek, Angus J. Robertson, Marie Jose Abi Saad, Miguel A. Trevino, Aikaterini C. Tsika, Fabio C. L. Almeida, Ad Bax, Katherine Henzler-Wildman, Jeffrey C. Hoch, Kristaps Jaudzems, Douglas Laurents, Julien Orts, Roberta Pierattelli, Georgios A. Spyroulias, Elke Duchardt-Ferner, Jan Ferner, Boris Furtig, Martin Hengesbach, Frank Lohr, Nusrat Qureshi, Christian Richter, Krishna Saxena, Andreas Schlundt, Sridhar Sreeramulu, Anna Wacker, Julia E. Weigand, Julia Wirmer-Bartoschek, Jens Wohnert, Harald Schwalbe
Summary: This study explores novel drug design against SARS-CoV-2 through NMR screening and computational mapping. They identified multiple molecules that bind to SARS-CoV-2 proteins and studied their structural and chemical properties, providing new insights for drug development.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
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
Biochemistry & Molecular Biology
Shamkhal Baybekov, Gilles Marcou, Pascal Ramos, Olivier Saurel, Jean-Luc Galzi, Alexandre Varnek
Summary: This paper reports comprehensive experimental and chemoinformatics analyses of the solubility of 939 fragments in dimethyl sulfoxide (DMSO), leading to the construction of a Support Vector Classification model with good performance in 5-fold cross-validation. Anomalous data points were identified and addressed, and both the datasets and the model are available for access.
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
Elena Shanina, Sakonwan Kuhaudomlarp, Eike Siebs, Felix F. Fuchsberger, Maxime Denis, Priscila da Silva Figueiredo Celestino Gomes, Mads H. Clausen, Peter H. Seeberger, Didier Rognan, Alexander Titz, Anne Imberty, Christoph Rademacher
Summary: Carbohydrate-protein interactions are crucial for cell-cell and host-pathogen recognition. This study identifies metal-binding pharmacophores as novel scaffolds for inhibiting Ca2+-dependent carbohydrate-protein interactions, addressing the challenge posed by the hydrophilic nature of these interactions.
COMMUNICATIONS CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Johanna H. M. Ehrler, Steffen Brunst, Amelie Tjaden, Whitney Kilu, Jan Heering, Victor Hernandez-Olmos, Andre Krommes, Jan S. Kramer, Dieter Steinhilber, Manfred Schubert-Zsilavecz, Susanne Muller, Daniel Merk, Ewgenij Proschak
Summary: This study presents the compilation and application of a focused screening library of fatty acid mimetics (FAMs), which are designed to bind proteins that accommodate natural fatty acids and lipid metabolites. Several hits were retrieved in screening the focused library against various fatty acid binding targets.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Merveille Eguida, Christel Schmitt-Valencia, Marcel Hibert, Pascal Villa, Didier Rognan
Summary: In this paper, we propose a computational approach called POEM to generate target-focused libraries using publicly available structural information on protein-ligand complexes. The approach involves aligning a collection of PDB-derived images with key shapes and pharmacophoric properties to the query target cavity using a computer vision method. The fragments from the most similar PDB subpockets are then positioned in the query cavity using corresponding image transformation matrices. Finally, a deep generative model is used to link suitable connectable atoms of oriented fragment pairs, resulting in fully connected molecules. We applied POEM to generate a library of potential cyclin-dependent kinase 8 inhibitors and achieved significant results with limited resources and only two iterative cycles.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ashima Chopra, Joseph D. Bauman, Francesc X. Ruiz, Eddy Arnold
Summary: X-ray crystallographic fragment screening (XCFS) utilizes fragment-sized molecules to access binding sites on proteins that may be inaccessible to larger drug-like molecules. This study focused on halogenated fragments, which have been shown to bind to proteins more frequently than non-halogenated fragments. The Halo Library containing 46 halogenated fragments was screened against HIV-1 reverse transcriptase crystals, resulting in the discovery of new binding sites and identification of hot spots. This small library can be a useful tool for quickly assessing target feasibility, mapping hot spots and cryptic sites, and finding fragment binders for drug lead development.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Geqing Wang, Biswaranjan Mohanty, Martin L. Williams, Bradley C. Doak, Rabeb Dhouib, Makrina Totsika, Roisin M. McMahon, Gaurav Sharma, Dan Zheng, Matthew R. Bentley, Yanni Ka-Yan Chin, James Horne, David K. Chalmers, Begona Heras, Martin J. Scanlon
Summary: DsbA enzymes play a crucial role in the oxidative folding of proteins in Gram-negative bacteria and have potential as a target for controlling bacterial virulence. This study identified a novel small molecule inhibitor that binds to the hydrophobic groove of VcDsbA with higher selectivity compared to EcDsbA. The crystal structures of VcDsbA and EcDsbA in complex with a known ligand revealed different binding modes and provided insights into ligand binding to these enzymes.
Article
Biochemical Research Methods
Guillaume A. Petit, Biswaranjan Mohanty, Roisin M. McMahon, Stefan Nebl, David H. Hilko, Karyn L. Wilde, Martin J. Scanlon, Jennifer L. Martin, Maria A. Halili
Summary: This study identified two fragments that bind to the DsbA protein from Burkholderia pseudomallei, providing a potential starting point for the development of more potent antimicrobial compounds.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2022)
Review
Biophysics
Stefan J. Hermans, Tracy L. Nero, Craig J. Morton, Jonathan H. Gooi, Gabriela A. N. Crespi, Nancy C. Hancock, Chen Gao, Kenta Ishii, Jasmina Markulic, Michael W. Parker
Summary: Alzheimer's disease is an age-related disease with no effective treatments. Cell surface receptors and immune system-related genes have been found to be associated with the disease risk. Structural biology has provided important insights into the functioning of these receptors.
BIOPHYSICAL REVIEWS
(2022)
Article
Multidisciplinary Sciences
Stanley C. Xie, Riley D. Metcalfe, Elyse Dunn, Craig J. Morton, Shih-Chung Huang, Tanya Puhalovich, Yawei Du, Sergio Wittlin, Shuai Nie, Madeline R. Luth, Liting Ma, Mi-Sook Kim, Charisse Flerida A. Pasaje, Krittikorn Kumpornsin, Carlo Giannangelo, Fiona J. Houghton, Alisje Churchyard, Mufuliat T. Famodimu, Daniel C. Barry, David L. Gillett, Sumanta Dey, Clara C. Kosasih, William Newman, Jacquin C. Niles, Marcus C. S. Lee, Jake Baum, Sabine Ottilie, Elizabeth A. Winzeler, Darren J. Creek, Nicholas Williamson, Michael W. Parker, Stephen Brand, Steven P. Langston, Lawrence R. Dick, Michael D. W. Griffin, Alexandra E. Gould, Leann Tilley
Summary: This study identifies aminoacyl transfer RNA synthetases as potential drug targets and presents a novel compound that can inhibit these enzymes, effectively killing the malaria parasite.
Article
Pharmacology & Pharmacy
Tim Quach, Luojuan Hu, Sifei Han, Shea F. Lim, Danielle Senyschyn, Preeti Yadav, Natalie L. Trevaksis, Jamie S. Simpson, Christopher J. H. Porter
Summary: Buprenorphine is a potent opioid analgesic that is widely used for pain management. However, its oral bioavailability is limited by first-pass metabolism. This study developed a prodrug strategy to enhance the oral bioavailability of buprenorphine through bypassing the liver and promoting drug release in plasma. The prodrug derivatives showed efficient transport into the lymphatics and significantly improved the oral bioavailability compared to buprenorphine alone. This research suggests the potential for developing an orally bioavailable buprenorphine product that may offer advantages in patient preference.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bronte A. Johnstone, Riya Joseph, Michelle P. Christie, Craig J. Morton, Conall McGuiness, James C. Walsh, Till Bocking, Rodney K. Tweten, Michael W. Parker
Summary: This review provides an overview of the characteristics and molecular mechanisms of cholesterol-dependent cytolysins (CDCs), and highlights the key questions that still need to be answered in order to better understand how these toxins kill cells.
Review
Pharmacology & Pharmacy
J. Zeller, B. Bogner, J. D. McFadyen, J. Kiefer, D. Braig, G. Pietersz, G. Krippner, T. L. Nero, C. J. Morton, K. S. Cheung Tung Shing, M. W. Parker, K. Peter, S. U. Eisenhardt
Summary: C-reactive protein (CRP) is not only a marker of inflammation and predictor of cardiovascular risk, but also a direct pathogenic pro-inflammatory mediator in atherosclerosis and cardiovascular diseases. The different conformations of the CRP system can aggravate tissue injury in pathological conditions, and studying the structural changes of CRP could be a novel therapeutic target for cardiovascular diseases and excessive inflammation.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Multidisciplinary Sciences
Nicole T. Eise, Jamie S. Simpson, Philip E. Thompson, Sabatino Ventura
Summary: Nettle leaf extract reduces prostatic smooth muscle contractility by acting as an antagonist at postjunctional P2X1-purinoceptors, leading to reduced male fertility in mice. However, cardiovascular parameters were unaffected, and no impact on mating behavior or organ weights was observed.
Article
Biology
Conall Mc Guinness, James C. Walsh, Charles Bayly-Jones, Michelle A. Dunstone, Michelle P. Christie, Craig J. Morton, Michael W. Parker, Till Bocking
Summary: This study investigates the assembly process of PFO in forming ring-shaped pores through single-molecule fluorescence imaging. The results show that the formation of PFO dimers promotes the growth of irreversible oligomers, and the insertion of oligomers and pore formation are influenced by the number of subunits.
Correction
Pharmacology & Pharmacy
Tim Quach, Luojuan Hu, Sifei Han, Shea F. Lim, Danielle Senyschyn, Preeti Yadav, Natalie L. Trevaskis, Jamie S. Simpson, Christopher J. H. Porter
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Medicine, Research & Experimental
Johannes Zeller, Karen S. Cheung Tung Shing, Tracy L. Nero, James D. McFadyen, Guy Krippner, Balazs Bogner, Sheena Kreuzaler, Jurij Kiefer, Verena K. Horner, David Braig, Habiba Danish, Sara Baratchi, Mark Fricke, Xiaowei Wang, Michel G. Kather, Bernd Kammerer, Kevin J. Woollard, Prerna Sharma, Craig J. Morton, Geoffrey Pietersz, Michael W. Parker, Karlheinz Peter, Steffen U. Eisenhardt
Summary: C-reactive protein (CRP) is highly upregulated during inflammatory reactions and exhibits pro-inflammatory effects. We discovered a mechanism in which CRP undergoes conformational changes, resulting in highly inflammatory forms. By designing a low molecular weight CRP inhibitor that mimics phosphocholine, we demonstrated its ability to inhibit CRP-driven inflammation while preserving its pathogen-defense functions. This represents a promising and potentially broad-spectrum anti-inflammatory therapy.
EMBO MOLECULAR MEDICINE
(2023)
Article
Virology
Leo Yi Yang Lee, Randy Suryadinata, Conor McCafferty, Vera Ignjatovic, Damian F. J. Purcell, Phil Robinson, Craig J. Morton, Michael W. Parker, Gary P. Anderson, Paul Monagle, Kanta Subbarao, Jessica A. Neil
Summary: The research found that heparin can effectively inhibit SARS-CoV-2 infection in nasal epithelial cells by blocking virus entry and replication. Additionally, the researchers developed a PCR detection method that can be used for virus detection in clinical studies.
Article
Chemistry, Medicinal
Luke A. Adams, Lorna E. Wilkinson-White, Menachem J. Gunzburg, Stephen J. Headey, Biswaranjan Mohanty, Martin J. Scanlon, Ben Capuano, Joel P. Mackay, Bradley C. Doak
Summary: A systematic workflow, called Rapid Elaboration of Fragments into Leads (REFiL), allows for the rapid improvement of binding affinity and evolution of low-affinity fragment hits into higher-affinity leads without the need for structural information.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Rebecca L. L. Whitehouse, Wesam S. S. Alwan, Olga V. V. Ilyichova, Ashley J. J. Taylor, Indu R. R. Chandrashekaran, Biswaranjan Mohanty, Bradley C. C. Doak, Martin J. J. Scanlon
Summary: Fragment-based drug design relies on structural information obtained through X-ray crystallography to evolve fragments into lead-like compounds through structure-based design. The composition of compound libraries can be optimized to probe binding hot spots on protein surfaces.
RSC MEDICINAL CHEMISTRY
(2023)
