Article
Chemistry, Medicinal
Theresa Kircher, Tatu Pantsar, Andreas Oder, Jens Peter von Kries, Michael Juchum, Bent Pfaffenrot, Philip Kloevekorn, Wolfgang Albrecht, Roland Selig, Stefan Laufer
Summary: MKK4 plays a key role in liver regeneration, making new small molecules inhibiting MKK4 potential candidates for treating acute and chronic liver diseases. Optimization of compound design led to the selection of fluorescent compounds with high binding affinities, with compound 45 identified as a suitable tool for studying new small-molecule inhibitors of MKK4.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Qian Chen, Junwei Zhou, Zhixiang Yang, Jiahui Guo, Zimin Liu, Xinyi Sun, Qingshi Jiang, Liurong Fang, Dang Wang, Shaobo Xiao
Summary: This study systematically investigated the substrate specificity switch mechanism of arterivirus 3CLpro and identified specific amino acid exchanges that can lead to the switch. These findings contribute to a better understanding of the biological characteristics and transmission mechanisms of arteriviruses and porcine reproductive and respiratory syndrome virus.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Nikhil K. Tulsian, Valerie Jia-En Sin, Hwee-Ling Koh, Ganesh S. Anand
Summary: PDEs hydrolyze cyclic nucleotides in cells and associate with PKs to form signalosomes, enhancing activity. Targeting PDE-PK complexes offers greater specificity and insights into cyclic nucleotide signaling networks in cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Christian Borgo, Luca Cesaro, Tsuyoshi Hirota, Keiko Kuwata, Claudio D'Amore, Thomas Ruppert, Renata Blatnik, Mauro Salvi, Lorenzo A. Pinna
Summary: CK2, a protein kinase with pleiotropic functions, is implicated in global human pathologies, particularly cancer. Selective inhibitors like CX4945 and GO289 show promise in controlling the CK2-dependent phosphoproteome.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Hanna Baltrukevich, Piia Bartos
Summary: This study investigates the differences in force fields when simulating RNA-protein complexes using molecular dynamics simulations. The results show that non-polarizable force fields lead to compact and stable complexes, while polarizable force fields allow for more movement but can result in complex disintegration.
FRONTIERS IN CHEMISTRY
(2023)
Article
Chemistry, Analytical
Pengfei Ma, Hualin Guo, Hua Ye, Yin Zhang, Zhouping Wang
Summary: In this study, the binding mechanism of a 19-base ZEN aptamer (Z19) with ZEN was systematically studied. The binding driving forces, key bases, conformational changes, and thermodynamic information were discovered. Based on this, a novel fluorescence polarization aptasensor was constructed using the rapid properties of fluorescence polarization and target recycling induced by Exo III. The aptasensor showed excellent analytical performance with a linear range of 0.01-100 ng/mL and a limit of detection as low as 0.004 ng/mL.
SENSORS AND ACTUATORS B-CHEMICAL
(2023)
Review
Biochemistry & Molecular Biology
Hieu Nguyen, Arminja N. Kettenbach
Summary: Dynamic protein phosphorylation and dephosphorylation play critical roles in cellular signaling and biological functions. Dysregulation of these processes has been linked to various human diseases. This review focuses on the mechanisms controlling the specific dephosphorylation of proteins. The majority of serine/threonine dephosphorylation is catalyzed by highly conserved phosphoprotein phosphatase (PPP) catalytic subunits, which form holoenzymes with regulatory and scaffolding subunits. PPP holoenzymes recognize phosphorylation site consensus motifs and interact with short linear motifs (SLiMs) or structural elements distal to the phosphorylation site. Recent advances in understanding the mechanisms of PPP site-specific dephosphorylation preference and substrate recruitment are discussed, with emphasis on their roles in regulating cell division.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Yao Chen, Bernardo L. Sabatini
Summary: In addition to inhibiting PKA activity, PKI was found to facilitate the activation of multiple isoforms of PKC at higher concentrations. This suggests the need for appropriate interpretation of experimental results when using PKI as a pharmaceutical agent. The study provides a foundation for exploring the potential functions of PKI in regulating PKC activity and coordinating PKC and PKA activities.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Wayde Veldman, Marcelo Vizona Liberato, Valquiria P. Souza, Vitor M. Almeida, Sandro R. Marana, Ozlem Tastan Bishop, Igor Polikarpov
Summary: This study investigates the structure and substrate specificity of a GH family 1 enzyme from Bacillus licheniformis, known as BlBglC, which has dual-phospho activity. The enzyme's broad specificity is attributed to specific inducing residues that bind strongly to different ligands, providing important details of its activity.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Rashid Waseem, Saleha Anwar, Shama Khan, Anas Shamsi, Md. Imtaiyaz Hassan, Farah Anjum, Alaa Shafie, Asimul Islam, Dharmendra Kumar Yadav
Summary: The study demonstrates that irisin binds to MARK4 and inhibits its activity, providing a new therapeutic approach for MARK4-associated diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Artur Meller, Jeffrey M. Lotthammer, Louis G. Smith, Borna Novak, Lindsey A. Lee, Catherine C. Kuhn, Lina Greenberg, Leslie A. Leinwand, Michael J. Greenberg, Gregory R. Bowman
Summary: The design of compounds that can discriminate between closely related target proteins remains a challenge in drug discovery. This study shows that the probability of pocket opening is an important determinant of the potency of the myosin inhibitor blebbistatin. By using Markov state models, it was found that the probability of pocket opening accurately identifies which isoforms are most sensitive to blebbistatin inhibition and predicts blebbistatin binding affinities.
Article
Biochemistry & Molecular Biology
Chang Liu, Zhizhen Li, Zonghan Liu, Shiye Yang, Qing Wang, Zongtao Chai
Summary: This study revealed the conformational dynamics of the phosphate-binding loop (P-loop) in different states of STK17B through molecular dynamics simulation. The interactions between the P-loop and inhibitors were found to contribute to inhibitor selectivity profile. These findings advance our understanding of kinase inhibitor selectivity and have implications for the design of selective inhibitors for other protein kinases.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Letter
Chemistry, Physical
Dan Su, Tatsiana Kosciuk, Hening Lin
Summary: This article concludes that binding affinity is crucial for in vivo substrate specificity and proposes a method to identify substrate proteins for enzymes by utilizing existing interactome data. The Reply aims to clarify important points in the original article.
Article
Biochemistry & Molecular Biology
Nehad Noby, Rachel L. Johnson, Jonathan D. Tyzack, Amira M. Embaby, Hesham Saeed, Ahmed Hussein, Sherine N. Khattab, Pierre J. Rizkallah, D. Dafydd Jones
Summary: The study on cold active esterase EstN7 reveals that its substrate range is limited but can be broadened through mutations, providing new insights for enzyme engineering.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Mohd Yousuf, Anas Shamsi, Shama Khan, Parvez Khan, Moyad Shahwan, Abdelbaset Mohamed Elasbali, Qazi Mohd Rizwanul Haque, Md Imtaiyaz Hassan
Summary: This study demonstrates that Naringenin (NAG) binds strongly to CDK6 and inhibits its activity. Cell-based experiments show that NAG decreases the cell viability of cancer cells, induces apoptosis, and reduces their colonization ability. These findings highlight the importance of NAG for the development of CDK6 inhibitors and combinatorial anti-cancer therapies.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Johana Hrdinova, Delia I. Fernandez, Bogac Ercig, Bibian M. E. Tullemans, Dennis P. L. Suylen, Stijn M. Agten, Kerstin Jurk, Tilman M. Hackeng, Karen Vanhoorelbeke, Jan Voorberg, Chris P. M. Reutelingsperger, Kanin Wichapong, Johan W. M. Heemskerk, Gerry A. F. Nicolaes
Summary: This study designed and synthesized stable cyclic peptides to interfere with the interaction between VWF A1 domain and GPIb alpha. The selected peptides showed low binding free energy and retained their interference in the binding of VWF to GPIb-V-IX, as confirmed by flow cytometry. These peptides phenotypically mimicked the changes seen with the anti-VWF A1 domain antibody CLB-RAg35, although they were less potent. The improved peptide opt-mono-ORbIT demonstrated increased inhibitory activity under flow.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Tanaporn Uengwetwanit, Nopporn Chutiwitoonchai, Kanin Wichapong, Nitsara Karoonuthaisiri
Summary: This study analyzed the amino acid sequence conservation of RNA-dependent RNA polymerase (RdRp) across coronaviruses and identified compounds with promising antiviral activity. Molecular dynamics simulations and binding free-energy calculations were performed to elucidate critical interactions, providing a foundation for developing lead compounds effective against SARS-CoV-2.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Jingnan Huang, Natalie J. Jooss, Delia Fernandez, Albert Sickmann, Angel Garcia, Kanin Wichapong, Ingrid Dijkgraaf, Johan W. M. Heemskerk
Summary: This study reveals a shear-dependent signaling axis of PTK2, integrin alpha IIb beta 3, and CIB1 in collagen- and GPVI-dependent thrombus formation, which is modulated by GPR56.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cardiac & Cardiovascular Systems
Katrin Nitz, Michael Lacy, Mariaelvy Bianchini, Kanin Wichapong, Irem Avcilar Kuecuekgoeze, Cecilia A. Bonfiglio, Roberta Migheli, Yuting Wu, Carina Burger, Yuanfang Li, Ignasi Forne, Constantin Ammar, Aleksandar Janjic, Sarajo Mohanta, Johan Duchene, Johan W. M. Heemskerk, Remco T. A. Megens, Edzard Schwedhelm, Stephan Huveneers, Craig A. Lygate, Donato Santovito, Ralf Zimmer, Axel Imhof, Christian Weber, Esther Lutgens, Dorothee Atzler
Summary: Amino acid homoarginine reduces atherosclerosis by modulating the T-cell cytoskeleton and inhibiting T-cell functions. This finding provides a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.
CIRCULATION RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Angelina Pavlic, Hessel Poelman, Grzegorz Wasilewski, Kanin Wichapong, Petra Lux, Cecile Maassen, Esther Lutgens, Leon J. Schurgers, Chris P. Reutelingsperger, Gerry A. F. Nicolaes
Summary: Vascular calcification (VC) is an important factor in cardiovascular diseases, mediated by the release of extracellular vesicles by vascular smooth muscle cells (VSMCs) and the enzyme nSMase2. Inhibitors of nSMase2 have been identified through virtual ligand screening, and two compounds (ID 5728450 and ID 4011505) were found to inhibit EV release and calcification in vitro, potentially serving as therapeutic drugs for VC treatment or prevention.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Medicine, General & Internal
Femke de Vries, Joram Huckriede, Kanin Wichapong, Chris Reutelingsperger, Gerry A. F. Nicolaes
Summary: This article reviews the cytotoxic mechanisms of extracellular histones in COVID-19 and discusses their role as potential drug targets and biomarkers. It provides important insights for the clinical treatment of COVID-19 patients.
JOURNAL OF INTERNAL MEDICINE
(2023)
Article
Orthopedics
A. Chabronova, G. G. H. van den Akker, B. A. C. Housmans, M. M. J. Caron, A. Cremers, D. A. M. Surtel, K. Wichapong, M. M. J. Peffers, L. W. van Rhijn, V. Marchand, Y. Motorin, T. J. M. Welting
Summary: This study investigates the role of ribosomes in chondrocyte translation regulation and its relevance for osteoarthritis. Using RiboMethSeq analysis, the researchers found that osteoarthritic synovial fluid induces site-specific changes in the rRNA 2'-O-me profile of primary human articular chondrocytes. These changes alter the translation mode and promote the translation of COL1A1 mRNA, leading to increased levels of COL1A1 protein and suggesting the involvement of rRNA epitranscriptomic mechanisms in osteoarthritis development.
OSTEOARTHRITIS AND CARTILAGE
(2023)
Editorial Material
Biochemistry & Molecular Biology
Wolfgang Sippl
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Mohamed Abdelsalam, Mariia Zmyslia, Karin Schmidtkunz, Anita Vecchio, Sebastian Hilscher, Hany S. Ibrahim, Mike Schutkowski, Manfred Jung, Claudia Jessen-Trefzer, Wolfgang Sippl
Summary: In this study, a series of prodrugs for class I histone deacetylases (HDACs) were designed and synthesized using known selective HDAC inhibitors. Compound 6 showed the most potent inhibitory activity against nitroreductase (NTR)-transfected leukemic cells.
ARCHIV DER PHARMAZIE
(2023)
Article
Oncology
Ramy Ashry, Al-Hassan M. Mustafa, Kristin Hausmann, Michael Linnebacher, Susanne Strand, Wolfgang Sippl, Matthias Wirth, Oliver H. Kraemer
Summary: Tumors in the pancreas and colon are still a clinical challenge. Different gene expression profiles between cancer cells and normal cells can be targeted by drugs that modulate protein acetylation. KH16 is a novel compound that induces hyperacetylation, leading to cell death in tumor cells while sparing normal cells. It shows superior efficacy compared to clinically established drugs. Further studies can focus on KH16 and similar compounds for cancer therapy.
Article
Chemistry, Medicinal
Emre F. F. Buelbuel, Dina Robaa, Ping Sun, Fereshteh Mahmoudi, Jelena Melesina, Matthes Zessin, Mike Schutkowski, Wolfgang Sippl
Summary: This study analyzed different ligand-based and structure-based drug design techniques to predict the binding mode and inhibitory activity of recently developed alkylhydrazide HDAC inhibitors. Alkylhydrazides have shown promising effects in various cancer cell lines. The created models, including pharmacophore models and atom-based quantitative structure-activity relationship (QSAR) models, explain in vitro data well and were used to develop novel HDAC3 inhibitors.
Article
Hematology
M. Christella L. G. D. Thomassen, Bryan R. C. Bouwens, Kanin Wichapong, Dennis P. Suylen, Freek G. Bouwman, Tilman M. Hackeng, Rory R. Koenen
Summary: This study found that PAD4 inactivates TFPI by citrullination of its arginines, and this process is time- and concentration-dependent. Furthermore, inducers of PAD4 blocked the citrullination of TFPI. This process may play a crucial role in the increased thrombosis risk associated with inflammation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Joram B. Huckriede, Danielle M. H. Beurskens, Karin C. C. A. Wildhagen, Chris P. M. Reutelingsperger, Kanin Wichapong, Gerry A. F. Nicolaes
Summary: This study investigated the interaction between human APC and human histone H3 and designed optimized APC variants through molecular docking and molecular dynamics simulation methods. The results showed that the designed APC variants had reduced anticoagulant activity, increased binding to histone H3, and similar ability to proteolyze histone H3 compared to the wild type-APC.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Biology
Fady Baselious, Dina Robaa, Wolfgang Sippl
Summary: In this study, we optimized the HDAC11 AlphaFold model by adding the catalytic zinc ion and successfully generated stable complexes for docking of selective inhibitors. The most reasonable pose was selected based on structural comparison, and the model explained the binding behavior of known HDAC11 inhibitors.
COMPUTERS IN BIOLOGY AND MEDICINE
(2023)
Review
Chemistry, Multidisciplinary
Conrad V. Simoben, Smith B. Babiaka, Aurelien F. A. Moumbock, Cyril T. Namba-Nzanguim, Donatus Bekindaka Eni, Jose L. Medina-Franco, Stefan Guenther, Fidele Ntie-Kang, Wolfgang Sippl
Summary: The use of traditional medicine has a long history and is still relied upon by many, especially in developing or underprivileged communities. In silico-based methods have played a crucial role in drug discovery, particularly in identifying natural product-based candidates. However, there are challenges in identifying and proposing novel natural product-based hits.
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
