keyword
https://read.qxmd.com/read/38546820/computational-investigation-of-the-covalent-inhibition-mechanism-of-bruton-s-tyrosine-kinase-by-ibrutinib
#1
JOURNAL ARTICLE
Angela M Barragan, Kyle Ghaby, Matthew P Pond, Benoît Roux
Covalent inhibitors represent a promising class of therapeutic compounds. Nonetheless, rationally designing covalent inhibitors to achieve a right balance between selectivity and reactivity remains extremely challenging. To better understand the covalent binding mechanism, a computational study is carried out using the irreversible covalent inhibitor of Bruton tyrosine kinase (BTK) ibrutinib as an example. A multi-μs classical molecular dynamics trajectory of the unlinked inhibitor is generated to explore the fluctuations of the compound associated with the kinase binding pocket...
March 28, 2024: Journal of Chemical Information and Modeling
https://read.qxmd.com/read/38543732/recent-advances-on-targeting-proteases-for-antiviral-development
#2
REVIEW
Pedro Henrique Oliveira Borges, Sabrina Baptista Ferreira, Floriano Paes Silva
Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible for causing diseases in humans, like the West Nile virus (WNV) and the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the mechanisms behind blocking viral protease's function is pivotal for the development of new antiviral drugs and therapeutical strategies...
February 27, 2024: Viruses
https://read.qxmd.com/read/38542870/selectivity-studies-and-free-energy-calculations-of-akt-inhibitors
#3
JOURNAL ARTICLE
Haizhen A Zhong, David T Goodwin
Protein kinase B (PKB) or AKT protein is an important target for cancer treatment. Significant advances have been made in developing ATP-competitive inhibitors and allosteric binders targeting AKT1. However, adverse effects or toxicities have been found, and the cutaneous toxicity was found to be linked to the inhibition of AKT2. Thus, selective inhibition of AKT inhibitors is of significance. Our work, using the Schrödinger Covalent Dock (CovDock) program and the Movable Type (MT)-based free energy calculation (ΔG), yielded small mean errors for the experimentally derived binding free energy (ΔG)...
March 10, 2024: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/38542207/targeting-btk-in-b-cell-malignancies-from-mode-of-action-to-resistance-mechanisms
#4
REVIEW
Samir Mouhssine, Nawar Maher, Bassam Francis Matti, Alaa Fadhil Alwan, Gianluca Gaidano
The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma...
March 12, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38537009/transient-receptor-potential-melastatin-7-trpm7-ion-channel-inhibitors-preliminary-sar-and-conformational-studies-of-xenicane-diterpenoids-from-the-hawaiian-soft-coral-sarcothelia-edmondsoni
#5
JOURNAL ARTICLE
Guangmin Yao, Matthew R Parris, W Cedric Kuo, Peter Pörzgen, Brandi Castillo, Evan S Mason, Andres Chinchilla, Junhao Huang, Sayuri Suzuki, Rylee Ross, Ellis Akana, Savana Vander Schuit, Steven P Miller, Reinhold Penner, Hong-Shuo Sun, Zhong-Ping Feng, Kenneth G Hull, Daniel Romo, Andrea Fleig, F David Horgen
Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni , is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni . In addition to known waixenicins A ( 1 ) and B ( 2 ), we purified six xenicane diterpenes, 7 S ,8 S -epoxywaixenicins A ( 3 ) and B ( 4 ), 12-deacetylwaixenicin A ( 5 ), waixenicin E ( 6 ), waixenicin F ( 7 ), and 20-acetoxyxeniafaraunol B ( 8 )...
March 27, 2024: Journal of Natural Products
https://read.qxmd.com/read/38536914/egfr-targeting-phostacs-as-a-dual-inhibitory-approach-reveals-differential-downstream-signaling
#6
JOURNAL ARTICLE
Zhenyi Hu, Po-Han Chen, Wenxue Li, Mackenzie Krone, Sijin Zheng, Jacques Saarbach, Ines Urquizo Velasco, John Hines, Yansheng Liu, Craig M Crews
We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and the active dephosphorylation by phosphatases to achieve dual inhibition of kinases. We report an example of tyrosine phosphatase-based TPDephos and the effective epidermal growth factor receptor (EGFR) tyrosine dephosphorylation. We also used phosphoproteomic approaches to study the signaling transductions affected by PhosTAC-related molecules at the proteome-wide level...
March 29, 2024: Science Advances
https://read.qxmd.com/read/38536576/bruton-tyrosine-kinase-inhibition-an-effective-strategy-to-manage-waldenstr%C3%A3-m-macroglobulinemia
#7
REVIEW
Reema K Tawfiq, Jithma P Abeykoon, Prashant Kapoor
PURPOSE OF REVIEW: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM...
March 27, 2024: Current Hematologic Malignancy Reports
https://read.qxmd.com/read/38531625/myeloperoxidase-inhibition-protects-bone-marrow-mononuclear-cells-from-dna-damage-induced-by-the-top2-poison-anti-cancer-drug-etoposide
#8
JOURNAL ARTICLE
Ian G Cowell, Caroline A Austin
Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation of reactive oxygen species that are important in anti-microbial action, but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti-cancer drugs, but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations...
March 26, 2024: FEBS Open Bio
https://read.qxmd.com/read/38530703/chemical-versatility-in-catalysis-and-inhibition-of-the-class-iib-histone-deacetylases
#9
JOURNAL ARTICLE
David W Christianson
ConspectusThe zinc-dependent histone deacetylases (HDACs 1-11) belong to the arginase-deacetylase superfamily of proteins, members of which share a common α/β fold and catalytic metal binding site. While several HDACs play a role in epigenetic regulation by catalyzing acetyllysine hydrolysis in histone proteins, the biological activities of HDACs extend far beyond histones. HDACs also deacetylate nonhistone proteins in the nucleus as well as the cytosol to regulate myriad cellular processes. The substrate pool is even more diverse in that certain HDACs can hydrolyze other covalent modifications...
March 26, 2024: Accounts of Chemical Research
https://read.qxmd.com/read/38527711/structural-and-kinetic-analysis-of-the-monofunctional-staphylococcus-aureus-pbp1
#10
JOURNAL ARTICLE
Christopher G Bon, Jason C Grigg, Jaeyong Lee, Craig S Robb, Nathanael A Caveney, Lindsay D Eltis, Natalie C J Strynadka
Staphylococcus aureus, an ESKAPE pathogen, is a major clinical concern due to its pathogenicity and manifold antimicrobial resistance mechanisms. The commonly used β-lactam antibiotics target bacterial penicillin-binding proteins (PBPs) and inhibit crosslinking of peptidoglycan strands that comprise the bacterial cell wall mesh, initiating a cascade of effects leading to bacterial cell death. S. aureus PBP1 is involved in synthesis of the bacterial cell wall during division and its presence is essential for survival of both antibiotic susceptible and resistant S...
March 23, 2024: Journal of Structural Biology
https://read.qxmd.com/read/38526531/exploring-the-efficacy-of-noncovalent-sars-cov-2-main-protease-inhibitors-a-computational-study-incorporating-design-admet-molecular-dynamics-simulation-and-dft-analysis
#11
JOURNAL ARTICLE
Fei Xiong, Yan-Jun Zhang, Hui-Ying Jiang, Zhong-Hua Wang
The SARS-CoV-2 main protease, as a key target for antiviral therapeutics, is instrumental in maintaining virus stability, facilitating translation, and enabling the virus to evade innate immunity. Our research focused on designing non-covalent inhibitors to counteract the action of this protease. Utilizing a 3D-QSAR model and contour map, we successfully engineered eight novel non-covalent inhibitors. Further evaluation and comparison of these novel compounds through methodologies including molecular docking, ADMET analysis, frontier molecular orbital studies, molecular dynamics simulations, and binding free energy revealed that the inhibitors N02 and N03 demonstrated superior research performance (N02 ΔGbind = -206...
March 25, 2024: Chemistry & Biodiversity
https://read.qxmd.com/read/38523661/the-c-terminal-selenenylsulfide-of-extracellular-non-reduced-thioredoxin-reductase-endows-this-protein-with-selectivity-to-small-molecule-electrophilic-reagents-under-oxidative-conditions
#12
JOURNAL ARTICLE
Huijun Qin, Chenchen Guo, Bozhen Chen, Hui Huang, Yaping Tian, Liangwei Zhong
Mammalian cytosolic thioredoxin reductase (TrxR1) serves as an antioxidant protein by transferring electrons from NADPH to various substrates. The action of TrxR1 is achieved via reversible changes between NADPH-reduced and non-reduced forms, which involves C-terminal selenolthiol/selenenylsulfide exchanges. TrxR1 may be released into extracellular environment, where TrxR1 is present mainly in the non-reduced form with active-site disulfide and selenenylsulfide bonds. The relationships between extracellular TrxR1 and tumor metastasis or cellular signaling have been discovered, but there are few reports on small-molecule compounds in targeted the non-reduced form of TrxR1...
2024: Frontiers in Molecular Biosciences
https://read.qxmd.com/read/38516702/metabolic-and-toxicological-considerations-of-bruton-s-tyrosine-kinase-inhibitors-for-the-treatment-of-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma
#13
REVIEW
Anna Wolska-Washer, Paweł Robak, Magdalena Witkowska, Tadeusz Robak
INTRODUCTION: Bruton tyrosine kinase inhibitors (BTKi) have been used for the management of human diseases since the approval of the first-in class agent, ibrutinib, by the Food and Drug Administration in 2013 for the treatment of patients with mantle cell lymphoma (MCL). Ibrutinib is a covalent inhibitor along with second-class BTKis: acalabrutinib and zanubrutinib. These well-tolerated agents have transformed the treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)...
March 22, 2024: Expert Opinion on Drug Metabolism & Toxicology
https://read.qxmd.com/read/38516589/unusual-ni%C3%A2-ni-interaction-in-ni-ii-complexes-as-potential-inhibitors-for-the-development-of-new-anti-sars-cov-2-omicron-drugs
#14
JOURNAL ARTICLE
Simranjeet Singh, Mukesh Choudhary
Two nickel(ii) coordination complexes [Ni(L)]2 (1) and [Ni(L)] n (2) of a tetradentate Schiff base ligand ( H 2 L ) derived from 2-hydroxy-1-naphthaldehyde with ethylenediamine were synthesized, designed, and characterized via spectroscopic and single crystal XRD analyses. Both nickel(ii) complexes exhibited unusual Ni⋯Ni interactions and were fully characterized via single-crystal X-ray crystallography. Nickel(ii) complexes [Ni(L)]2 (1) and [Ni(L)] n (2) crystallize in monoclinic and triclinic crystal systems with P 21 / c and P 1̄ space groups, respectively, and revealed square planar geometry around each Ni(ii) ion...
March 20, 2024: RSC medicinal chemistry
https://read.qxmd.com/read/38513196/discovery-of-a-covalent-inhibitor-selectively-targeting-the-autophosphorylation-site-of-c-src-kinase
#15
JOURNAL ARTICLE
Huimin Zhang, Dounan Xu, Hongchan Huang, Hao Jiang, Linghao Hu, Liping Liu, Ge Sun, Jing Gao, Yuanqing Li, Cuicui Xia, Shijie Chen, Hu Zhou, Xiangqian Kong, Mingliang Wang, Cheng Luo
Nonreceptor tyrosine kinase c-Src plays a crucial role in cell signaling and contributes to tumor progression. However, the development of selective c-Src inhibitors turns out to be challenging. In our previous study, we performed posttranslational modification-inspired drug design (PTMI-DD) to provide a plausible way for designing selective kinase inhibitors. In this study, after identifying a unique pocket comprising a less conserved cysteine and an autophosphorylation site in c-Src as well as a promiscuous covalent inhibitor, chemical optimization was performed to obtain ( R )-LW-Srci-8 with nearly 75-fold improved potency (IC50 = 35...
March 21, 2024: ACS Chemical Biology
https://read.qxmd.com/read/38506362/-diagnosis-and-treatment-of-elevated-lipoprotein-a-in-israel-consensus-statement-from-the-israel-society-for-research-prevention-and-treatment-of-atherosclerosis-and-israel-society-for-clinical-laboratory-sciences
#16
JOURNAL ARTICLE
Barak Zafrir, Ronen Durst, Clara Henig, Yaakov Henkin, Elena Itzhakov, Marielle Kaplan, Dov Gavish
Lipoprotein(a) [Lp(a)] is composed of 2 major protein components, a low-density lipoprotein (LDL) cholesterol-like particle containing apolipoprotein B (apo B) that is covalently bound to apolipoprotein(a). Its level is predominantly genetically determined, and it is estimated that 20% to 25% of the population have Lp(a) levels that are associated with increased cardiovascular risk. Elevated Lp(a) is related to increased vascular inflammation, calcification, atherogenesis and thrombosis, and is considered an independent and potentially causal risk factor for atherosclerotic cardiovascular diseases and calcified aortic valve stenosis...
March 2024: Harefuah
https://read.qxmd.com/read/38502552/molecular-insights-into-the-impact-of-mutations-on-the-binding-affinity-of-targeted-covalent-inhibitors-of-btk
#17
JOURNAL ARTICLE
Ernest Awoonor-Williams, Abd Al-Aziz A Abu-Saleh
Targeted covalent inhibitors (TCIs) have witnessed a significant resurgence in recent years, particularly in the kinase drug discovery field for treating diverse clinical indications. The inhibition of Bruton's tyrosine kinase (BTK) for treating B-cell cancers is a classic example where TCIs such as ibrutinib have had breakthroughs in targeted therapy. However, selectivity remains challenging, and the emergence of resistance mutations is a critical concern for clinical efficacy. Computational methods that can accurately predict the impact of mutations on inhibitor binding affinity could prove helpful in informing targeted approaches─providing insights into drug resistance mechanisms...
March 19, 2024: Journal of Physical Chemistry. B
https://read.qxmd.com/read/38502195/a-phase-1-study-of-the-irreversible-flt3-inhibitor-ff-10101-in-relapsed-or-refractory-acute-myeloid-leukemia
#18
JOURNAL ARTICLE
Mark J Levis, Alexander E Perl, Gary J Schiller, Amir T Fathi, Gail J Roboz, Eunice S Wang, Jessica K Altman, Trivikram Rajkhowa, Makoto Ando, Takeaki Suzuki, Ruth Ann Subach, Gary Maier, Timothy Madden, Mary Johansen, Kin Cheung, Michael Kurman, Catherine C Smith
FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and unlike other inhibitors is minimally vulnerable to resistance induced by FLT3 ligand (FL)...
March 19, 2024: Blood Advances
https://read.qxmd.com/read/38502038/a-chloromethyl-triazole-fluorescent-chemosensor-for-o-6-methylguanine-dna-methyltransferase
#19
JOURNAL ARTICLE
Seylan Ayan, Adrian M Rotaru, Esther G Kaye, Gabrielle Juneau, Sunit Das, Christopher J Wilds, Andrew A Beharry
Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6 -methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT...
March 19, 2024: Organic & Biomolecular Chemistry
https://read.qxmd.com/read/38500384/a-biological-guide-to-glycosaminoglycans-current-perspectives-and-pending-questions
#20
REVIEW
Sylvie Ricard-Blum, Romain R Vivès, Liliana Schaefer, Martin Götte, Rosetta Merline, Alberto Passi, Paraskevi Heldin, Ana Magalhães, Celso A Reis, Spyros S Skandalis, Nikos K Karamanos, Serge Perez, Dragana Nikitovic
Mammalian glycosaminoglycans (GAGs), except hyaluronan (HA), are sulfated polysaccharides that are covalently attached to core proteins to form proteoglycans (PGs). This article summarizes key biological findings for the most widespread GAGs, namely HA, chondroitin sulfate/dermatan sulfate (CS/DS), keratan sulfate (KS), and heparan sulfate (HS). It focuses on the major processes that remain to be deciphered to get a comprehensive view of the mechanisms mediating GAG biological functions. They include the regulation of GAG biosynthesis and postsynthetic modifications in heparin (HP) and HS, the composition, heterogeneity, and function of the tetrasaccharide linkage region and its role in disease, the functional characterization of the new PGs recently identified by glycoproteomics, the selectivity of interactions mediated by GAG chains, the display of GAG chains and PGs at the cell surface and their impact on the availability and activity of soluble ligands, and on their move through the glycocalyx layer to reach their receptors, the human GAG profile in health and disease, the roles of GAGs and particular PGs (syndecans, decorin, and biglycan) involved in cancer, inflammation, and fibrosis, the possible use of GAGs and PGs as disease biomarkers, and the design of inhibitors targeting GAG biosynthetic enzymes and GAG-protein interactions to develop novel therapeutic approaches...
March 18, 2024: FEBS Journal
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