Article
Chemistry, Inorganic & Nuclear
Chengfeng Zhu, A-Mei Zhang, Ying Li, Han-Xue Li, Yijian Qian, Yanming Fu, Xiang Wu, Yougui Li
Summary: A chiral metal-organic framework (CMOF) with accessible binding pockets and multiple recognition sites was constructed using a tricarboxylate ligand derived from phenylalanine. The CMOF has a rare structure with cavities encapsulated by a non-coordinated amino-acid moiety. It has been proven to be an efficient and recyclable chiral host, capable of adsorbing and separating racemic alcohols, diols, and epoxides with excellent enantioselectivity.
INORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Medicinal
Ute F. Rohrig, Mathilde Goullieux, Marine Bugnon, Vincent Zoete
Summary: Molecular docking is a computational approach used to predict the position of a ligand in the binding site of a target molecule. The AC 2.0 docking algorithm has been improved to provide more robust sampling and flexibility. Experimental testing shows that AC 2.0 performs well in both redocking and cross-docking tasks, achieving good enrichment factors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemical Research Methods
Zheng-Chang Lu, Fan Jiang, Yun-Dong Wu
Summary: Phosphate binding is crucial in biological processes, and accurate prediction of phosphate binding sites is challenging. The novel PBSP method, combining energy-based ligand-binding sites identification and reverse focused docking with a phosphate probe, outperforms existing predictors with high success rates and accuracy in phosphate binding modes prediction.
Article
Biochemistry & Molecular Biology
Ma'mon M. Hatmal, Omar Abuyaman, Mutasem Taha
Summary: In this study, the use of multiple docked poses for machine learning-based QSAR modelling was introduced to discover potential inhibitors of the serine protease enzyme TMPRSS2. Xgboost, SVM, and RF were found to be the best machine learners with testing set accuracies reaching 90%. Three potential hits were identified by scanning known untested FDA approved drugs against TMPRSS2. Subsequent molecular dynamics simulation and covalent docking supported the new computational approach's results.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Cillian Variot, Daniel Capule, Xhulio Arolli, Jackson Baumgartner, Cory Reidl, Charles Houseman, Miguel A. Ballicora, Daniel P. Becker, Misty L. Kuhn
Summary: In this study, we investigated how the PA3944 enzyme from Pseudomonas aeruginosa recognizes different acceptor substrates and identified critical residues for substrate specificity. By mutating seven amino acid residues to alanine, we determined their effects on the kinetic parameters of PA3944. We found that certain residues improved the affinity and catalytic efficiency of PA3944 towards NANMO and/or polymyxin B. Additionally, one mutant (R106A) showed substrate inhibition towards NANMO, and we propose potential reasons for this inhibition based on further substrate docking studies with R106A.
Article
Chemistry, Medicinal
Emilia P. Barros, Benjamin Ries, Candide Champion, Salome R. Rieder, Sereina Riniker
Summary: Macromolecular recognition and ligand binding are crucial for biological function and drug discovery. Water molecules play an important role in mediating protein-ligand interactions, affecting the binding process. However, current computational methods neglect the solvent correlation effects when replacing water clusters. In this study, we rigorously investigate the effects of replacing water molecules in protein binding pockets and demonstrate the importance of considering solvation effects on ligand binding and selectivity in computer-aided drug discovery.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Sami T. Kurkinen, Jukka Lehtonen, Olli T. Pentikainen, Pekka A. Postila
Summary: R-NiB and BR-NiB methods optimize docking prediction models, significantly improving docking efficacy by filtering active compounds from inactive ones. These optimized models contain only the most vital information for filtering docked compounds effectively.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Lim Heo, Sangwoo Park, Chaok Seok
Summary: The article presents a novel method, GalaxyWater-wKGB, for predicting water positions on the protein surface, based on a statistical potential incorporating the generalized Born model. This method is accurate and rapid due to the effective statistical treatment, providing a more precise description of specific protein atom-water interactions compared to traditional methods.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Materials Science, Multidisciplinary
Vinod K. Gangwar, Shiv Kumar, Mahima Singh, Debarati Pal, Labanya Ghosh, Prajyoti Singh, Zhang Yufeng, Chaoyu Chen, Eike F. Schwier, Kenya Shimada, Prashant Shahi, Yoshiya Uwatoko, Swapnil Patil, Anup K. Ghosh, Sandip Chatterjee
Summary: The study investigated the different roles of surface and bulk states in Bi1.9Dy0.1Te3 topological insulators through electronic states, magnetotransport properties, Seebeck coefficient, and magnetization. A significant magnetoresistance value of around 1500% at a magnetic field of 7T was attributed to the surface state. The magnetization behavior indicated the presence of an antiferromagnetic state, while the observed anomalous Hall effect was established as the contribution from the bulk state.
JOURNAL OF MATERIALS CHEMISTRY C
(2022)
Article
Chemistry, Medicinal
Sangwoo Park, Chaok Seok
Summary: This study uses the Galaxy-Water convolutional neural network to accurately predict the locations of water molecules in proteins based on structural data. Compared to previous energy-based methods, it shows significant improvement in accuracy and coverage.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Xiao-Long Liu, Zhe-Ran Wu, Wang Liao, Xiao-Qing Zhang, Yi-Wen Pei, Min Lu
Summary: This study investigated the function and binding properties of two general odorant binding proteins (GOBPs) in Spodoptera frugiperda. It was found that SfruGOBP1 had binding affinities to a few volatiles and insecticides, while SfruGOBP2 showed a broader ligand-binding spectrum, suggesting its importance in perceiving host volatiles. Molecular docking and site-directed mutagenesis assays provided insight into the key amino acid residues involved in the binding of insecticides to the GOBPs. This study offers valuable information for understanding the olfactory mechanism of GOBPs in S. frugiperda.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Fisheries
Shiyong Yang, Sizhu Leng, Yunkun Li, Xiaoai Wang, Yuanwei Zhang, Anli Wu, Yanfeng Gao, Jiayun Wu, Xianyin Zeng, Xiaogang Du, Xiaofu Pan
Summary: Two family members of TLR5, sgTLR5a and sgTLR5b, were identified in Sinocyclocheilus grahami, with the ability to play an important role in antibacterial response by activating the NF-Kappa B signaling pathway to recognize bacterial flagellin and Aeromonas hydrophila.
FISH & SHELLFISH IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Andrea Pasquadibisceglie, Fabio Polticelli
Summary: SLC25A29 in mitochondria is responsible for the translocation of basic amino acids. Nitric oxide levels from amino acid metabolism can affect cancer cells' metabolic status, while metabolic diseases related to mitochondrial dysregulation can be improved by reducing the activity of SLC25A29. Structural analysis of SLC25A29 has provided insights into ligands recognition and interaction critical for binding and translocation.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Immunology
Jiacheng Li, Yugang Fu, Kehui Zhang, Yong Li
Summary: Based on membrane tension-related genes, this study developed a prognostic model for colon cancer and identified TIMP1 as a potential regulator of colon cancer progression. The 4-gene signature showed promise as a biomarker for predicting clinical outcomes. The study also explored the relationships between the signature and immune cell infiltration, immune status, and somatic mutation, as well as the drug sensitivity of TIMP-1.
Article
Chemistry, Inorganic & Nuclear
Rashid G. Siddique, Kasun S. A. Arachchige, Hydar A. AL-Fayaad, John C. McMurtrie, Jack K. Clegg
Summary: The outcomes of self-assembly reactions are influenced by the interplay of multiple factors. Here, utilizing an acetylene-appended quaterpyridine ligand, it is demonstrated that the size of the metal ion and steric repulsion between the acetylene groups exclusively lead to the formation of [M2L3] helicates instead of a helicate/tetrahedron equilibrium.
DALTON TRANSACTIONS
(2022)
Article
Biochemical Research Methods
Robert A. Nicholls, Robbie P. Joosten, Fei Long, Marcin Wojdyr, Andrey Lebedev, Eugene Krissinel, Lucrezia Catapano, Marcus Fischer, Paul Emsley, Garib N. Murshudov
Summary: This article discusses the protocols and tools for modelling covalent linkages within the CCP4 suite, including the generation of link dictionaries and the use of various tools for covalent linkage modelling. These integrated solutions streamline the workflow and aim to improve the quality of future modelled covalent linkages.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2021)
Article
Biochemical Research Methods
Robert A. Nicholls, Marcin Wojdyr, Robbie P. Joosten, Lucrezia Catapano, Fei Long, Marcus Fischer, Paul Emsley, Garib N. Murshudov
Summary: This study evaluates the issues with covalent linkages in the Protein Data Bank, aiming to remediate existing models and improve the quality of future linkages. By analyzing the CCP4 Monomer Library, it is found that failure to model a covalent linkage results in inaccurate interatomic distances. The recent expansion of the CCP4-ML with additional dictionaries and link dictionaries will aid in identifying and applying linkage types in future modeling efforts.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2021)
Article
Hematology
Yunchao Chang, Jaeki Min, Jamie A. Jarusiewicz, Marisa Actis, Shanshan Yu-Chen Bradford, Anand Mayasundari, Lei Yang, Divyabharathi Chepyala, Lisa J. Alcock, Kathryn G. Roberts, Stanley Nithianantham, Dylan Maxwell, Lauren Rowland, Randolph Larsen, Aman Seth, Hiroaki Goto, Toshihiko Imamura, Koshi Akahane, Baranda S. Hansen, Shondra M. Pruett-Miller, Elisabeth M. Paietta, Mark R. Litzow, Chunxu Qu, Jun J. Yang, Marcus Fischer, Zoran Rankovic, Charles G. Mullighan
Summary: The study evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) against JAKs, and developed multiple PROTACs that could degrade JAKs and effectively inhibit CRLF2r cell lines, with one compound showing the potential to suppress the proliferation of CRLF2r ALL in vivo. This highlights the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT-driven ALL.
Article
Chemistry, Medicinal
Gisele Nishiguchi, Fatemeh Keramatnia, Jaeki Min, Yunchao Chang, Barbara Jonchere, Sourav Das, Marisa Actis, Jeanine Price, Divyabharathi Chepyala, Brandon Young, Kevin McGowan, P. Jake Slavish, Anand Mayasundari, Jamie A. Jarusiewicz, Lei Yang, Yong Li, Xiang Fu, Shalandus H. Garrett, James B. Papizan, Kiran Kodali, Junmin Peng, Shondra M. Pruett Miller, Martine F. Roussel, Charles Mullighan, Marcus Fischer, Zoran Rankovic
Summary: This study describes the design, synthesis, and screening of a large diverse library of thalidomide analogues against leukemia and medulloblastoma cell lines, leading to the discovery of potent GSPT1/2 degraders with selectivity over IMiD neosubstrates and high oral bioavailability in mice. Compound 6 (SJ6986) is proposed as a valuable tool for studying the role of GSPT1/2 and supports the utility of a diverse library of CRBN binders in targeting undruggable oncoproteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Huda Zahid, Caroline R. Buchholz, Manjulata Singh, Michael F. Ciccone, Alice Chan, Stanley Nithianantham, Ke Shi, Hideki Aihara, Marcus Fischer, Ernst Schonbrunn, Camila O. dos Santos, Joseph W. Landry, William C. K. Pomerantz
Summary: This study describes the development of pyridazinone-based BPTF inhibitors, with the lead compound BZ1 showing high potency and selectivity over BET bromodomains. The inhibitors sensitized breast cancer cells to doxorubicin, indicating specificity to BPTF. The findings suggest that these inhibitors could serve as starting points for exploring the biological roles of BPTF.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Jaeki Min, Anand Mayasundari, Fatemeh Keramatnia, Barbara Jonchere, Seung Wook Yang, Jamie Jarusiewicz, Marisa Actis, Sourav Das, Brandon Young, Jake Slavish, Lei Yang, Yong Li, Xiang Fu, Shalandus H. Garrett, Mi-Kyung Yun, Zhenmei Li, Stanley Nithianantham, Sergio Chai, Taosheng Chen, Anang Shelat, Richard E. Lee, Gisele Nishiguchi, Stephen W. White, Martine F. Roussel, Patrick Ryan Potts, Marcus Fischer, Zoran Rankovic
Summary: IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, affecting their efficacy; Novel CRBN binders, phenyl glutarimide (PG) analogues, were designed with high affinity and improved stability; Discovery of PG PROTAC 4c as a potent degrader of BET proteins, supporting the utility of PG derivatives in CRBN-directed PROTACs design.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Lisa J. Alcock, Yunchao Chang, Jamie A. Jarusiewicz, Marisa Actis, Stanley Nithianantham, Anand Mayasundari, Jaeki Min, Dylan Maxwell, Jeremy Hunt, Brandon Smart, Jun J. Yang, Gisele Nishiguchi, Marcus Fischer, Charles G. Mullighan, Zoran Rankovic
Summary: The study describes the design and synthesis of JAK2/3 PROTACs and their potency in patient-derived ALL cells. SJ10542 showed high selectivity and potency, making it a promising candidate for the treatment of hematological malignancies.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Timothy R. Stachowski, Murugendra Vanarotti, Jayaraman Seetharaman, Karlo Lopez, Marcus Fischer
Summary: High-resolution crystal structures have shown the importance of water networks in protein-ligand interactions. This study compares room-temperature and cryogenic datasets to identify changes in water networks that affect protein conformations and ligand interactions. The results reveal temperature and ligand-sensitive regions in the protein structure, providing insights for discovering selective ligands and utilizing hidden protein and water conformations in drug discovery.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Medicinal
Timothy R. Stachowski, Marcus Fischer
Summary: Protein flexibility is crucial in drug design, especially for targeting dynamic proteins like Hsp90. The analysis of Hsp90 alpha crystal structures revealed different conformations of the lid domain that accommodate chemically distinct ligands. This study highlights the importance of considering protein ensembles and warns against overinterpreting individual crystal structures in drug design.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Hematology
Yunchao Chang, Fatemeh Keramatnia, Pankaj S. Ghate, Gisele Nishiguchi, Qingsong Gao, Ilaria Iacobucci, Lei Yang, Divyabharathi Chepyala, Ashutosh Mishra, Anthony A. High, Hiroaki Goto, Koshi Akahane, Junmin Peng, Jun J. Yang, Marcus Fischer, Zoran Rankovic, Charles G. Mullighan
Summary: This study developed a novel cereblon modulator named SJ6986, which effectively degrades GSPT1 and GSPT2 and exhibits cytotoxic activity against childhood cancer cell lines. In vitro and in vivo testing showed that SJ6986 has similar cytotoxicity to the previously described GSPT1 degrader CC-90009, but is more effective in suppressing leukemic cell growth and does not significantly impair differentiation of human CD34(+) cells. Genome-wide CRISPR/Cas9 screening confirmed the involvement of components of the CRL4CRBN complex in mediating the action of SJ6986. SJ6986 is a potent and selective GSPT1/2 degrader with broad antileukemic activity and potential for clinical development.
Article
Chemistry, Medicinal
Mladen Koravovic, Anand Mayasundari, Gordana Tasic, Fatemeh Keramatnia, Timothy R. Stachowski, Huarui Cui, Sergio C. Chai, Barbara Jonchere, Lei Yang, Yong Li, Xiang Fu, Ryan Hiltenbrand, Leena Paul, Vibhor Mishra, Jeffery M. Klco, Martine F. Roussel, William CK. Pomerantz, Marcus Fischer, Zoran Rankovic, Vladimir Savic
Summary: An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired the synthesis of JQ1 derived heterocyclic amides. These compounds displayed improved profiles compared to JQ1 and birabresib as potent BET inhibitors. A specific compound 1q (SJ1461) showed excellent affinity to both BRD4 and BRD2 and high potency in acute leukaemia and medulloblastoma cell lines. The co-crystal structure of 1q with BRD4-BD1 revealed polar interactions, explaining the observed affinity improvements. Furthermore, pharmacokinetic studies suggested that the heterocyclic amide moiety improved drug-like features. Our study led to the discovery of the potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Timothy R. R. Stachowski, Stanley Nithianantham, Murugendra Vanarotti, Karlo Lopez, Marcus Fischer
Summary: Isoforms of HSP90 play a role in facilitating cancer development, but their therapeutic potential remains unfulfilled due to lack of FDA-approved drugs. The challenge lies in selective targeting of isoforms with high structural similarity and side effects caused by pan-HSP90 inhibition. This study presents a three-pronged approach to understand the HSP90 landscape and explore isoform-specific accommodations, shedding light on ligand discovery and design for potential drug development.
Article
Biochemical Research Methods
Timothy R. Stachowski, Marcus Fischer
Summary: Researchers have developed an automated multi-conformer modeling program, FLEXR, to detect and include hidden protein conformational dynamics in high-resolution electron-density maps. The program reveals new structural details that are missed by manual modeling or current tools, such as hidden side chains and backbone conformations in ligand-binding sites, which may redefine protein-ligand binding mechanisms. FLEXR is an open-source tool available for crystallographers.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Shanshan Y. C. Bradford, Lea El Khoury, Yunhui Ge, Meghan Osato, David L. Mobley, Marcus Fischer
Summary: By systematically investigating protein conformational changes in response to temperature and ligand binding, new global and local structural changes were revealed in the T4 lysozyme L99A cavity when shifting to room temperature. Temperature-induced alterations in protein and ligand structures can influence computational methods and the utility of structural information in ligand binding predictions, highlighting the potential limitations of relying solely on cryogenic data for computational purposes.
Review
Biophysics
Marcus Fischer
Summary: This review discusses practical aspects of preparing, acquiring, and analyzing X-ray crystallography data at room temperature, aiming to demystify preconceived impracticalities that freeze progress of routine room temperature data collection at synchrotron sources. Examples are provided as conceptual and experimental templates, illustrating the diversity and utility of gaining novel insights into protein conformational landscapes. An integrative view of protein conformational dynamics offers opportunities to advance basic and biomedical research.
QUARTERLY REVIEWS OF BIOPHYSICS
(2021)