Article
Biochemistry & Molecular Biology
Neeladri Sen, Mallur S. Madhusudhan
Summary: In this study, a structural library of 178,465 interfaces mediating protein-protein/domain-domain interactions was created from the PDB. Analysis of the library revealed similarities between chain-chain and domain-domain interactions, as well as the ability of a single protein fold to interact with multiple folds using similar interfaces. The library provides a valuable resource for studying protein fold interactions and identifying potential binding partners. Additionally, statistical potentials of amino acid pair preferences were constructed for chain-chain and domain-domain interactions, further supporting the use of domain-domain interfaces in studying chain-chain interactions. The library also includes predicted small molecule-binding sites at protein-protein interfaces, which could have applications in therapeutic strategies.
Review
Biochemistry & Molecular Biology
Orsolya Toke
Summary: Disorders in bile acid transport and metabolism are associated with metabolic diseases, atherosclerosis, type-II diabetes, and cancer. Bile acid-binding proteins (BABPs) play a crucial role in cellular trafficking and metabolic targeting of bile salts. Understanding the structure and function of BABPs provides insights for the design and development of drugs targeting bile salt transport.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemical Research Methods
Lin Gu, Bin Li, Dengming Ming
Summary: In this study, a multilayer dynamics perturbation analysis (MDPA) method was proposed to predict ligand-binding regions on protein surface based on protein structure. The MDPA method showed good prediction performance, accurately predicting ligand-binding sites in most cases, and was compared with other state-of-the-art structure prediction methods.
BMC BIOINFORMATICS
(2022)
Article
Biochemistry & Molecular Biology
Bing Bai, Rongfeng Zou, H. C. Stephen Chan, Hongchun Li, Shuguang Yuan
Summary: Protein-ligand interaction analysis is crucial for drug discovery and rational protein design. MolADI, an online tool, provides detailed analysis of these interactions and allows easy viewing with 2D graphs and 3D representations. It focuses on interactions that evolve over time.
Article
Multidisciplinary Sciences
Yuki Toyama, Robert W. Harkness, Lewis E. Kay
Summary: This study investigates the interaction between HtrA2 and protein substrates using NMR spectroscopy and finds that HtrA2 binds to substrates through two parts, and multivalent binding significantly stimulates its catalytic activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Soichiro Kawagoe, Koichiro Ishimori, Tomohide Saio
Summary: Despite recent developments, the process of protein folding, especially the folding of multidomain proteins, remains poorly understood. Molecular chaperones play a crucial role in assisting the folding of multidomain proteins, but the detailed mechanisms are still unclear. This review summarizes the biophysical and structural studies on the mechanism of molecular chaperone-mediated multidomain protein folding, as well as the recognition and alteration of client protein folding properties by molecular chaperones.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Giorgos Gouridis, Yusran A. Muthahari, Marijn de Boer, Douglas A. Griffith, Alexandra Tsirigotaki, Konstantinos Tassis, Niels Zijlstra, Ruixue Xu, Nikolaos Eleftheriadis, Yovin Sugijo, Martin Zacharias, Alexander Domling, Spyridoula Karamanou, Charalambos Pozidis, Anastassios Economou, Thorben Cordes
Summary: Novel biophysical tools have allowed exploration of protein structural dynamics and evolution, revealing how modifications of structural cores can lead to diversification of protein functions. The mechanism uncovered in this study provides insights into the emergence of functional promiscuity during long periods of evolution, with implications for a wide range of domain architectures.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Catriona M. A. Thompson, Richard H. Little, Clare E. M. Stevenson, David M. Lawson, Jacob G. Malone
Summary: This study reveals the regulatory mechanism of the RimK system in bacteria and the structural differences among different bacteria, providing insights into the impact of protein sequence and structure on protein activity.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Review
Biochemistry & Molecular Biology
Aleksandra A. Kuznetsova, Olga S. Fedorova, Nikita A. Kuznetsov
Summary: DNA polymerases play a crucial role in DNA replication, repair, and recombination. This review provides a comprehensive overview of the catalytic mechanism of DNA polymerases, describing the structural features of different families and discussing the kinetics and conformational dynamics during DNA synthesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Francini Fonseca Lopez, Jiayuan Miao, Jovan Damjanovic, Luca Bischof, Michael B. Braun, Yingjie Ling, Marcus D. Hartmann, Yu-Shan Lin, Joshua A. Kritzer
Summary: The Nrf2 transcription factor regulates the response to oxidative stress, and Keap1 is its main negative regulator. This study used molecular dynamics simulations to predict the preorganization of cyclic peptides and correlated it with binding affinities for Keap1. The findings provide insights into designing selective inhibitors of protein-protein interactions using cyclic peptides.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Kenshiro Hirata, Akito Kawai, Victor Tuan Giam Chuang, Keiki Sakurama, Koji Nishi, Keishi Yamasaki, Masaki Otagiri
Summary: The study found that myristate can affect the induced circular dichroism spectra of aripiprazole bound to human serum albumin, and can displace aripiprazole molecules from albumin.
Review
Pharmacology & Pharmacy
Stephen J. Hill, Laura E. Kilpatrick
Summary: Equilibrium binding assays are commonly used in drug discovery to evaluate drug-receptor interactions, but there is increasing interest in studying the kinetics of these interactions. Drugs can induce conformational changes in the orthosteric binding site, leading to alterations in the association and dissociation rates of orthosteric ligands. This review provides an overview of how fluorescent ligand technologies are used to study ligand-receptor kinetics in living cells and the insights they offer into conformational changes induced by drugs targeting cell surface receptors.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Mathematical & Computational Biology
Yekai Zhou, Hongjun Chen, Sida Li, Ming Chen
Summary: The study focuses on databases with structural information of protein-protein interactions, developing a database extension called mPPI for PPI structural visualization. Compared to existing databases, mPPI can display target proteins and their multiple interactors simultaneously, aiding in multi-target drug discovery and protein macro-complex structure prediction.
DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION
(2021)
Article
Chemistry, Multidisciplinary
Bo Cai, Casey J. Krusemark
Summary: A novel assay method combining DNA encoding with split-and-pool sample handling is developed to improve small-molecule binding assays to target proteins. The approach involves affinity labeling of DNA-linked ligands to a protein target, allowing for quantification of DNA barcodes to detect ligand binding. This method demonstrates potential utility in high-throughput small-molecule screening.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Medicinal
Timofey V. Losev, Igor S. Gerasimov, Maria V. Panova, Alexey A. Lisov, Yana R. Abdyusheva, Polina V. Rusina, Eugenia Zaletskaya, Oleg V. Stroganov, Michael G. Medvedev, Fedor N. Novikov
Summary: Bioisosteres are molecules with different substituents but similar shapes. They are widely used in drug design to modify metabolism, bioavailability, and activity. However, predicting the affinity of bioisosteres with computational methods has been challenging due to their similarity to standard force fields. In this study, a quantum mechanical (QM)-cluster approach based on the GFN2-xTB method was developed and successfully applied to predict the biological activity change of H -> F bioisosteric replacements. The method showed superior accuracy compared to the ChemPLP scoring function and comparable to in vitro experiments, with a standard deviation of 0.60 kcal/mol.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Engineering, Industrial
Angelo K. S. Romasanta, Peter van der Sijde, Iwan J. P. de Esch
Summary: This study explores how researchers in big pharma firms engage with knowledge from an emerging field, and how they adapt their activities to overcome uncertainties. By focusing on internal and external activities, proponents of novel technologies bridge the developments in the field with the rest of the firm, leading to the adoption and development of the technology.
Article
Chemistry, Medicinal
Iwan J. P. de Esch, Daniel A. Erlanson, Wolfgang Jahnke, Christopher N. Johnson, Louise Walsh
Summary: The review summarizes successful fragment-to-lead studies published in 2020 and discusses trends and best practices in fragment libraries, target proteins, screening technologies, hit-optimization strategies, and properties of hit fragments and leads. Trends and innovations identified in the review promise to further increase the success of FBDD by developing novel screening fragments, improving screening technologies, using computer-aided design and virtual screening, and combining FBDD with other drug-discovery technologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
David J. Hamilton, Marieke Beemsterboer, Caroline M. Carter, Jasmina Elsayed, Rilana E. M. Huiberts, Hanna F. Klein, Peter O'Brien, Iwan J. P. de Esch, Maikel Wijtmans
Summary: Fragment-based drug discovery has a growing need for unique screening libraries. Cyclobutane moiety, identified as an attractive three-dimensional scaffold, was used to synthesize a library of novel 3D cyclobutane fragments. The library exhibited favorable shape and physicochemical properties compared to existing synthetic 3D fragment libraries.
Article
Chemistry, Medicinal
Lorena Zara, Francesca Moraca, Jacqueline E. Van Muijlwijk-Koezen, Barbara Zarzycka, Robert Abel, Iwan J. P. de Esch
Summary: This study evaluated a method for predicting drug affinity in the treatment of African trypanosomiasis. The researchers found that this method accurately predicted the activity of different proteins and overcame challenges such as protein flexibility and sequence conservation. Therefore, this method holds promise for designing more selective inhibitors for African trypanosomes.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Hendrik J. Brink, Rick Riemens, Stephanie Thee, Berend Beishuizen, Daniel da Costa Pereira, Maikel Wijtmans, Iwan de Esch, Martine J. Smit, Albertus H. de Boer
Summary: In this study, a fragment-based drug screening approach was used to identify a PPI stabilizer targeting 14-3-3. The stabilizer was found to cooperatively stabilize 14-3-3 and enhance its binding to client proteins. This finding provides a tool compound for investigating the interactions between 14-3-3 and client proteins.
Article
Chemistry, Medicinal
Gabor Wagner, Tamara A. M. Mocking, Xiaoyuan Ma, Inna Slynko, Daniel Da Costa Pereira, Robin Breeuwer, Niek J. N. Rood, Cas van der Horst, Henry F. Vischer, Chris de Graaf, Iwan J. P. de Esch, Maikel Wijtmans, Rob Leurs
Summary: In this study, the structure-activity relationship analysis of derivatives of ZEL-H16 revealed that both basic moieties and their distance from the central core are essential for H3R affinity. However, contrary to previous reports, ZEL-H16 and its derivatives were found to act as inverse agonists for G alpha(i) signaling in this study. Docking studies and molecular dynamics simulations identified ionic interactions/hydrogen bonds as crucial interaction points with H3R residues D114 and E206.
ARCHIV DER PHARMAZIE
(2023)
Article
Biochemistry & Molecular Biology
Yang Zheng, Susanne Schroeder, Georgi K. Kanev, Sanaa S. Botros, Samia William, Abdel-Nasser A. Sabra, Louis Maes, Guy Caljon, Carmen Gil, Ana Martinez, Irene G. Salado, Koen Augustyns, Ewald Edink, Maarten Sijm, Erik de Heuvel, Iwan J. P. de Esch, Tiffany van der Meer, Marco Siderius, Geert Jan Sterk, David Brown, Rob Leurs
Summary: This study investigated the potential of Schistosoma mansoni phosphodiesterase SmPDE4A as a new drug target for schistosomiasis. The researchers cloned, isolated, and characterized the full-length and catalytic domains of SmPDE4A. They found that SmPDE4A resembles human PDE4 more than parasite PDEs. Screening of PDE inhibitors identified tetrahydrophthalazinones and benzamides as potential hits, but further evaluation showed that the inhibitors were not effective against S. mansoni, suggesting that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Tom Dekker, Jaap W. W. Harteveld, Gabor Wagner, Max C. M. de Vries, Hans Custers, Andrea C. van de Stolpe, Iwan J. P. de Esch, Maikel Wijtmans
Summary: Biomass-derived molecules have the potential for sustainable drug discovery, but their exploration is hindered by the dominance of old-fashioned screening compounds in classical high-throughput screening libraries. We propose a fragment-based drug discovery approach as an efficient method to navigate biomass-derived drug space. In a proof-of-concept study using dihydrolevoglucosenone (Cyrene TM), we generated a diverse fragment library with good physicochemical properties and potential for novel drug candidates based on renewable resources.
Article
Multidisciplinary Sciences
Andrei Rajkovic, Sandesh Kanchugal, Eldar A. Abdurakhmanov, Rebecca Howard, Sebastian Warmlander, Joseph Erwin, Hugo A. Barrera Saldana, Astrid Graslund, Helena Danielson, Samuel Coulbourn Flores
Summary: The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has important implications in cancer and growth disorders, and hGH has been engineered to improve its binding properties. This study focuses on the E174 substitution in hGH, which has been shown to increase binding but lacks an explanation. The results suggest that the E174A substitution increases affinity of hGH against hGHR by slowing down the off-rate more than the on-rate, highlighting the link between structure, zinc binding, and hGHR-binding affinity in hGH.
Article
Multidisciplinary Sciences
Zhongxuan Ma, K. D. Augustijn, I. J. P. De Esch, B. A. G. Bossink
Summary: This study investigates the micro-foundations of dynamic capabilities in university technology transfer through qualitative case studies at two organizations. The micro-foundations of sensing include selecting internal competency and sensing external partners, while seizing involves resource co-allocation and collaborative business model. The micro-foundations of reconfiguring include strategic renewal, establishing a university technology transfer-friendly environment, and asset orchestration. This study provides better understanding of how dynamic capabilities facilitate university technology transfer, and offers suggestions for industrial practitioners and policymakers.
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
Icaro A. Simon, Evert J. Homan, Maikel Wijtmans, Michael Sundstrom, Rob Leurs, Iwan J. P. De Esch, Barbara A. Zarzycka
Summary: The researchers have developed an open-source computational platform, called PSW-Designer, for the design and screening of new photoswitchable ligands, especially for GPCRs. Through two case studies, they validate the predictive capabilities of the platform and anticipate that it will facilitate the design of improved photoswitchable molecules.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Mostafa Fekry, Khyati K. Dave, Dilip Badgujar, Emil Hamnevik, Oskar Aurelius, Doreen Dobritzsch, U. Helena Danielson
Summary: Tyrosinases are enzymes involved in melanin production, and the vsTyr is a unique bacterial tyrosinase that does not require a caddie protein and shares similarity with plant-derived members of the enzyme family.
Article
Oncology
Nadilly Bonagas, Nina M. S. Gustafsson, Martin Henriksson, Petra Marttila, Robert Gustafsson, Elisee Wiita, Sanjay Borhade, Alanna C. Green, Karl S. A. Vallin, Antonio Sarno, Richard Svensson, Camilla Gokturk, Therese Pham, Ann-Sofie Jemth, Olga Loseva, Victoria Cookson, Nicole Kiweler, Lars Sandberg, Azita Rasti, Judith E. Unterlass, Martin Haraldsson, Yasmin Andersson, Emma R. Scaletti, Christoffer Bengtsson, Cynthia B. J. Paulin, Kumar Sanjiv, Eldar Abdurakhmanov, Linda Pudelko, Ben Kunz, Matthieu Desroses, Petar Iliev, Katarina Farnegardh, Andreas Kramer, Neeraj Garg, Maurice Michel, Sara Haggblad, Malin Jarvius, Christina Kalderen, Amanda Bogedahl Jensen, Ingrid Almlof, Stella Karsten, Si Min Zhang, Maria Haggblad, Anders Eriksson, Jianping Liu, Bjorn Glinghammar, Natalia Nekhotiaeva, Fredrik Klingegard, Tobias Koolmeister, Ulf Martens, Sabin Llona-Minguez, Ruth Moulson, Helena Nordstrom, Vendela Parrow, Leif Dahllund, Birger Sjoberg, Irene L. Vargas, Duy Duc Vo, Johan Wannberg, Stefan Knapp, Hans E. Krokan, Per Arvidsson, Martin Scobie, Johannes Meiser, Pal Stenmark, Ulrika Warpman Berglund, Evert J. Homan, Thomas Helleday
Summary: This study investigates the role of MTHFD2 in cancer cells and the effects of its inhibitors. The results demonstrate that MTHFD2 inhibitors can decrease DNA replication speed, induce replication stress, and ultimately lead to apoptosis in cancer cells. These findings reveal the functional link between MTHFD2-dependent cancer metabolism and replication stress, providing a potential therapeutic strategy.
Article
Biochemistry & Molecular Biology
Susanne Mueller, Suzanne Ackloo, Arij Al Chawaf, Bissan Al-Lazikani, Albert Antolin, Jonathan B. Baell, Hartmut Beck, Shaunna Beedie, Ulrich A. K. Betz, Gustavo Arruda Bezerra, Paul E. Brennan, David Brown, Peter J. Brown, Alex N. Bullock, Adrian J. Carter, Apirat Chaikuad, Mathilde Chaineau, Alessio Ciulli, Ian Collins, Jan Dreher, David Drewry, Kristina Edfeldt, Aled M. Edwards, Ursula Egner, Stephen Frye, Stephen M. Fuchs, Matthew D. Hall, Ingo Hartung, Alexander Hillisch, Stephen H. Hitchcock, Evert Homan, Natarajan Kannan, James R. Kiefer, Stefan Knapp, Milka Kostic, Stefan Kubicek, Andrew R. Leach, Sven Lindemann, Brian D. Marsden, Hisanori Matsui, Jordan L. Meier, Daniel Merk, Maurice Michel, Maxwell R. Morgan, Anke Mueller-Fahrnow, Dafydd R. Owen, Benjamin G. Perry, Saul H. Rosenberg, Kumar Singh Saikatendu, Matthieu Schapira, Cora Scholten, Sujata Sharma, Anton Simeonov, Michael Sundstrom, Giulio Superti-Furga, Matthew H. Todd, Claudia Tredup, Masoud Vedadi, Frank von Delft, Timothy M. Willson, Georg E. Winter, Paul Workman, Cheryl H. Arrowsmith
Summary: Twenty years after the first draft of the human genome was published, our understanding of the human proteome is still incomplete. The majority of proteins in the human proteome remain uncharacterized, with only a small percentage successfully targeted for drug discovery. Target 2035 aims to bridge this gap by developing new technologies for the entire human proteome by 2035.
RSC MEDICINAL CHEMISTRY
(2022)
