Article
Multidisciplinary Sciences
Sani Muhammad Uzairu, Yahaya Tijani, Madu Adamu Gadaka, Babagana Modu, Miriam Watafua, Hadiza Ali Ahmad, Umar Abdullahi Zakariya, Aminu Ibrahim, Aliyu Daja, Hassan Zanna, Abdullahi Balarabe Sallau
Summary: The study reveals the potential of methylrosmarinate as a good inhibitor of BChE and its possible therapeutic application in Alzheimer's disease. Using molecular docking simulations and experimental validation, the research elucidates the mechanism and structural features of methylrosmarinate-BChE interactions.
Review
Biochemistry & Molecular Biology
Azis Boing Sitanggang, Jessica Eka Putri, Nurheni Sri Palupi, Emmanuel Hatzakis, Elvira Syamsir, Slamet Budijanto
Summary: This study presents a systematic review on the enzymatic preparation of Angiotensin-I-Converting Enzyme inhibitory (ACEi) peptides, with soybeans and velvet beans identified as suitable sources for producing these peptides. Specific enzymatic conditions for producing ACEi peptides from soybeans and peptide hydrolysates with high ACEi activity are discussed in detail. Additionally, the study highlights the importance of molecular sizes, amino acid residues, and positions in determining the activity of ACEi peptides derived from soybeans.
Article
Biochemical Research Methods
Suqing Wang, Meizi Wang, Jingjing Cui, Di Lian, Li Li
Summary: Okanin, a major flavonoid in Coreopsis tinctoria Nutt., a popular herb tea, was found to strongly inhibit CYP3A4 and CYP2D6. Through enzyme kinetics, multispectral technique, and molecular docking, it was determined that the interaction between okanin and CYPs was significant. Okanin exhibited mixed inhibition on CYP3A4 and non-competitive inhibition on CYP2D6. The binding constant and IC50 values indicated a stronger interaction between okanin and CYP3A4 compared to CYP2D6. Okanin induced conformational changes in both CYP3A4 and CYP2D6. Fluorescence measurement and molecular docking confirmed the binding of okanin to these enzymes through hydrogen bonds and hydrophobic forces. The study suggests that okanin consumption should be cautious due to its potential to interact with drugs through inhibiting CYP3A4 and CYP2D6 activities.
JOURNAL OF FLUORESCENCE
(2023)
Article
Engineering, Chemical
Mehmet Abdullah Alagoz, Seong-Min Kim, Jong Min Oh, Gulnur Arslan, Zeynep Ozdemir, Suat Sari, Azime Berna Ozcelik, Tijen Onkol, Daniela Trisciuzzi, Orazio Nicolotti, Hoon Kim, Bijo Mathew
Summary: Thirteen benzothiazolone derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases and monoamine oxidases. The compounds showed stronger inhibitory activity towards cholinesterases, particularly butyrylcholinesterase. Among the compounds, M13 exhibited the most potent inhibition against butyrylcholinesterase and may be a potential candidate for Alzheimer's disease treatment.
Article
Biochemistry & Molecular Biology
Md Yousof Ali, Sumera Zaib, Susoma Jannat, Imtiaz Khan, M. Mizanur Rahman, Seong Kyu Park, Mun Seog Chang
Summary: The study demonstrates the potential of certain ginsenosides in combating diabetes by effectively inhibiting enzyme activities, preventing sorbitol accumulation, and providing a new perspective for the development of therapeutic agents for diabetic complications.
Article
Chemistry, Inorganic & Nuclear
Arturo Rodriguez-Banqueri, Marina Moliner-Culubret, Soraia R. Mendes, Tibisay Guevara, Ulrich Eckhard, F. Xavier Gomis-Ruth
Summary: The study obtained a low-resolution crystal structure of proulilysin and found that Ulilysin from Methanosarcina acetivorans can be inhibited by 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). The crystal structure of the complex revealed that the inhibitor mimics the basic side chain of substrates and penetrates the specificity pocket of ulilysin.
DALTON TRANSACTIONS
(2023)
Article
Chemistry, Medicinal
Yuguang Zhao, Fredrik Svensson, David Steadman, Sarah Frew, Amy Monaghan, Magda Bictash, Tiago Moreira, Rod Chalk, Weixian Lu, Paul Fish, E. Yvonne Jones
Summary: Notum inhibitors can restore Wnt signaling which may be therapeutic for diseases such as osteoporosis and Alzheimer's. A novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4oxobutanoate esters, and their covalent adduct formation mechanisms were identified. Insights into the inhibition of Notum catalysis could lead to the development of more potent inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biology
Yang Dong, Jiali Wang, Rachel-Ann Garibsingh, Keino Hutchinson, Yueyue Shi, Gilad Eisenberg, Xiaozhen Yu, Avner Schlessinger, Christof Grewer, Randy B. Stockbridge
Summary: EAAT1 is a glutamate transporter that regulates extracellular glutamate concentration in the brain, while ASCT2 is an amino acid transporter involved in the movement of glutamine between intracellular and extracellular compartments. Both transporters belong to the SLC1 family and share a similar mechanism of allosteric modulation, as discovered through experimental and computational studies.
Article
Multidisciplinary Sciences
Mateusz Dyla, Nicolas S. Gonzalez Foutel, Daniel E. Otzen, Magnus Kjaergaard
Summary: This study investigates how the affinity of docking interactions in kinases affects enzymatic activity and how to choose the optimal docking module to complement a given substrate. Equations predicting the optimal binding strength of a kinase docking interaction were developed and validated using numerical simulations and steady-state phosphorylation kinetics.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Danish Iqbal, M. Salman Khan, Mohd Waiz, Md Tabish Rehman, Mohammed Alaidarous, Azfar Jamal, Abdulaziz S. Alothaim, Mohamed F. AlAjmi, Bader Mohammed Alshehri, Saeed Banawas, Mohammed Alsaweed, Yahya Madkhali, Abdulrahman Algarni, Suliman A. Alsagaby, Wael Alturaiki
Summary: Geraniol is a competitive inhibitor of AChE with a high binding affinity, as shown by in vitro and in silico studies. Docking and molecular dynamics simulations confirmed the stable conformation of geraniol in the binding cavity of AChE, suggesting its potential as a natural compound for neurological and neuromuscular disorders.
Article
Biochemistry & Molecular Biology
Keyvan Pedrood, Maedeh Sherafati, Maryam Mohammadi-Khanaposhtani, Mohammad Sadegh Asgari, Samanesadat Hosseini, Hossein Rastegar, Bagher Larijani, Mohammad Mahdavi, Parham Taslimi, Yavuz Erden, Sevilay Gunay, Ilhami Gulcin
Summary: Novel quinazolinone derivatives were synthesized and evaluated for their inhibitory activities against various metabolic enzymes, showing high inhibitory activities. The most potent compounds against each enzyme were selected to evaluate their interaction modes in the active site, while cytotoxicity assays demonstrated that these compounds do not exhibit significant cytotoxic effects on cancer cell lines.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Ramazan Kalin, Zeynep Koksal, Songul Bayrak, Serpil Gerni, Isil Nihan Ozyurek, Hande Usanmaz, Muhammet Karaman, Ali Atasever, Hasan Ozdemir, Ilhami Gulcin
Summary: This study tested the inhibition effects of several antibiotics on lactoperoxidase (LPO) and found that cefazolin exhibited the strongest inhibitory efficacy. The study also identified the key role of the 5-methyl-1,3,4-thiadiazol-2-yl moiety in the inhibition mechanism of cefazolin.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Jie-Hao Xu, Jinhyuk Lee, Shang-Jun Yin, Wei Wang, Yong-Doo Park
Summary: This study investigates the tyrosinase inhibitory activity of acarbose and reveals its reversible binding mechanism as a distinctive mixed-type inhibitor. The findings also show that acarbose gradually inactivates the catalytic function of tyrosinase in a time-dependent manner and causes structural deformation in the catalytic site pocket. Computational docking simulation identifies key residues involved in the binding of acarbose to tyrosinase. This study highlights the potential of acarbose as an alternative whitening agent for the treatment of skin hyperpigmentation disorders.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biology
Usman Ghani, Sajda Ashraf, Zaheer Ul Haq, Zafer Asim Kaplancikli, Fatih Demirci, Yusuf Ozkay, Sibtain Afzal
Summary: Isomerism plays a crucial role in determining the efficacy, selectivity, and inhibition type of enzyme inhibitors. This study presents new alpha-glucosidase inhibitors with positional isomerism of the methyl group at the 3rd and 4th positions of their piperidine ring. The isomerism affects the interaction between the inhibitors and the enzyme, influencing their potency and selectivity. The 4-methyl derivatives establish more and stronger molecular contacts with the enzyme, leading to higher selectivity, while the isomerism does not significantly affect the inhibition type, with most compounds exhibiting noncompetitive inhibition.
COMPUTATIONAL BIOLOGY AND CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Cuneyt Turkes, Yeliz Demir, Sukru Beydemir
Summary: The study found that some calcium channel blockers may act as potential inhibitors of hCA I and hCA II, with nimodipine showing the best performance. These compounds could be useful in developing new CA inhibitors.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Chemistry, Medicinal
Magdalena M. Scharf, Mirjam Zimmermann, Florian Wilhelm, Raimond Stroe, Maria Waldhoer, Peter Kolb
Article
Biochemical Research Methods
Ismael Rodriguez-Espigares, Mariona Torrens-Fontanals, Johanna K. S. Tiemann, David Aranda-Garcia, Juan Manuel Ramirez-Anguita, Tomasz Maciej Stepniewski, Nathalie Worp, Alejandro Varela-Rial, Adrian Morales-Pastor, Brian Medel-Lacruz, Gaspar Pandy-Szekeres, Eduardo Mayol, Toni Giorgino, Jens Carlsson, Xavier Deupi, Slawomir Filipek, Marta Filizola, Jose Carlos Gomez-Tamayo, Angel Gonzalez, Hugo Gutierrez-de-Teran, Mireia Jimenez-Roses, Willem Jespers, Jon Kapla, George Khelashvili, Peter Kolb, Dorota Latek, Maria Marti-Solano, Pierre Matricon, Minos-Timotheos Matsoukas, Przemyslaw Miszta, Mireia Olivella, Laura Perez-Benito, Davide Provasi, Santiago Rios, Ivan R. Torrecillas, Jessica Sallander, Agnieszka Sztyler, Silvana Vasile, Harel Weinstein, Ulrich Zachariae, Peter W. Hildebrand, Gianni De Fabritiis, Ferran Sanz, David E. Gloriam, Arnau Cordomi, Ramon Guixa-Gonzalez, Jana Selent
Article
Biochemistry & Molecular Biology
Denis Schmidt, Magdalena M. Scharf, Dominique Sydow, Eva Assmann, Maria Marti-Solano, Marina Keul, Andrea Volkamer, Peter Kolb
Summary: The article discusses the challenges of achieving selectivity in designing ligands targeting human kinases and the importance of considering multi-target kinase ligands while avoiding binding to anti-targets. The study used in silico docking to identify novel small molecule ligands with pre-defined binding profiles for a series of kinase targets and anti-targets, and found that the hit rates were low in this specific setup. Only one specific substance was verified as a successful dual-specific EGFR/ErbB2 ligand that avoided binding to the anti-target BRAF. Further analysis and strategies were re-evaluated based on these findings, emphasizing the importance of considering hit rates in a multi-target drug discovery effort.
Article
Biochemistry & Molecular Biology
Joshua J. Hamey, Sinja Rakow, Caroline Bouchard, Johanna M. Senst, Peter Kolb, Uta-Maria Bauer, Marc R. Wilkins, Gene Hart-Smith
Summary: PRMT6 catalyzes the asymmetric dimethylation of arginines on substrate proteins, including histone H3, affecting gene regulation. This study systematically characterized PRMT6's substrate recognition motif, showing broad specificity and a preference for the RG motif. Despite efficient methylation at H3R2, PRMT6 tolerates various amino acid substitutions in the H3 peptide, with preference for positively charged and bulky residues near the target arginine.
Review
Pharmacology & Pharmacy
Peter Kolb, Terry Kenakin, Stephen P. H. Alexander, Marcel Bermudez, Laura M. Bohn, Christian S. Breinholt, Michel Bouvier, Stephen J. Hill, Evi Kostenis, Kirill A. Martemyanov, Rick R. Neubig, H. Ongun Onaran, Sudarshan Rajagopal, Bryan L. Roth, Jana Selent, Arun K. Shukla, Martha E. Sommer, David E. Gloriam
Summary: GPCRs regulate various physiological processes and their effects depend on the pairing of a receptor and a ligand. Ligands that induce biased signalling can lead to better drug effects and fewer side effects. However, ligand bias is complex, making it necessary to develop guidelines for designing and reporting biased signalling experiments.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biology
Anja Floeser, Katharina Becker, Evi Kostenis, Gabriele Konig, Cornelius Krasel, Peter Kolb, Moritz Buenemann
Summary: The study compared the efficacy of seven agonists in inducing interactions with M3 muscarinic acetylcholine receptors, finding substantial differences in the induction of M3R-arrestin3 versus M3R-GRK2 interaction.
Article
Multidisciplinary Sciences
Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Buenemann, Peter Kolb
Summary: Researchers computationally describe alternative allosteric pockets in G-protein-coupled receptors, identifying nine previously untargeted sites for synthetic ligands. They further investigate the potential of modulating receptor function through ligand binding to these sites.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Hannes Schihada, Thomas M. Klompstra, Laura J. Humphrys, Igor Cervenka, Shamim Dadvar, Peter Kolb, Jorge L. Ruas, Gunnar Schulte
Summary: The G protein-coupled receptor GPR35 is involved in oncogenic signaling, bacterial infections, and inflammatory bowel disease within the intestine. This study reveals that GPR35 has two isoforms with distinct promoters and alternative splicing. The longer isoform limits G protein activation but enhances receptor-beta-arrestin interaction. Structural analysis suggests that a disulfide bridge between the N-terminus and extracellular loop 3 is crucial for G protein activation, while an additional cysteine from the extended N-terminus of the longer isoform limits agonist-induced receptor-beta-arrestin2 interaction. The findings provide insights for developing isoform-specific GPR35 ligands for mechanism-based therapies.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Margherita Persechino, Janik Bjoern Hedderich, Peter Kolb, Daniel Hilger
Summary: G protein-coupled receptors (GPCRs) are important targets for drug development, and allosteric modulators offer new avenues for regulating their function. Recent advances in determining the structures of GPCRs bound to allosteric modulators have enhanced our understanding of their interactions and will facilitate the discovery of novel therapeutic candidates.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Chemistry, Medicinal
Lukas Heyder, Phil M. M. Hochban, Corey Taylor, Florent Chevillard, Christof Siefker, Christian Iking, Hannes Borchardt, Achim Aigner, Gerhard Klebe, Andreas Heine, Peter Kolb, Wibke E. Diederich
Summary: In this study, fragment-sized hits binding to Pim-1 kinase were optimized using a combination of computational, synthetic, and crystallographic expertise. The resulting potent ligands target rarely-targeted regions of Pim-1 kinase with affinities in the nanomolar range. The combination of computational and experimental approaches successfully developed a novel molecular scaffold for inhibition of Pim-1 kinase, targeting specific surface regions that have been less frequently investigated.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Tobias Benkel, Mirjam Zimmermann, Julian Zeiner, Sergi Bravo, Nicole Merten, Victor Jun Yu Lim, Edda Sofie Fabienne Matthees, Julia Drube, Elke Miess-Tanneberg, Daniela Malan, Martyna Szpakowska, Stefania Monteleone, Jak Grimes, Zsombor Koszegi, Yann Lanoiselee, Shannon O'Brien, Nikoleta Pavlaki, Nadine Dobberstein, Asuka Inoue, Viacheslav Nikolaev, Davide Calebiro, Andy Chevigne, Philipp Sasse, Stefan Schulz, Carsten Hoffmann, Peter Kolb, Maria Waldhoer, Katharina Simon, Jesus Gomeza, Evi Kostenis
Summary: This study provides an alternative mechanism for carvedilol's cellular signaling, demonstrating that G proteins drive all detectable signals through beta(2)-adrenoceptors.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Merlin Bresinsky, Aida Shahraki, Peter Kolb, Steffen Pockes, Hannes Schihada
Summary: In this study, a signaling pathway-independent readout of compound-GPR3 interaction was developed, providing new cues for the pharmacological manipulation of GPR3 activity. This has significant implications for the future development of drugs targeting these pharmacologically attractive oGPCRs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Niklas Rosier, Denise Moennich, Martin Nagl, Hannes Schihada, Alexei Sirbu, Nergis Konar, Irene Reyes-Resina, Gemma Navarro, Rafael Franco, Peter Kolb, Paolo Annibale, Steffen Pockes
Summary: Dopamine D-1-like receptors are the most abundant type of dopamine receptors in the central nervous system. The synthesis of new fluorescent ligands derived from D1R antagonist SCH-23390 was described, which can be used as tools for the visualization of D-1-like receptors. The high-affinity ligand UR-NR435 (25) showed excellent selectivity towards D-1-like receptors and proved to be a neutral antagonist in binding studies. This fluorescent ligand is a useful tool for studying native D-1 receptors in various experimental setups.
Article
Biochemistry & Molecular Biology
Martin Nagl, Denise Moennich, Niklas Rosier, Hannes Schihada, Alexei Sirbu, Nergis Konar, Irene Reyes-Resina, Gemma Navarro, Rafael Franco, Peter Kolb, Paolo Annibale, Steffen Pockes
Summary: This study describes the synthesis of a set of new fluorescent ligands for visualization of dopamine D-2-like receptors. The ligand UR-MN212 (20) showed high affinity for D-2-like receptors and moderate selectivity towards D-1-like receptors. It displayed rapid association with D2longR and can be used for fluorescence microscopy studies. The ligand's binding affinity was determined in a single-digit nanomolar range, consistent with radioligand binding data.
Article
Chemistry, Multidisciplinary
Florent Chevillard, Adam Kelemen, Jillian G. Baker, Vivien A. Aranyodi, Frank Balzer, Peter Kolb, Gyorgy M. Keseru
Summary: A new docking-based fragment evolution approach was developed to extend orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluation of 13,000 extensions for beta(1)- and beta(2)-adrenergic receptors resulted in the synthesis and testing of 112 bitopic molecules, confirming the positive contribution of the secondary binding pocket to potency and selectivity optimizations.
CHEMICAL COMMUNICATIONS
(2021)