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- Glycosaminoglycans (2)
- 857; BETA-CHEMOKINE; AMINO-ACIDS; INFECTION; ASTROCYTES (1)
- ACTH‐independent Cushing's syndrome (1)
- Allosteric inhibitors (1)
- Anti-cancer (1)
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- Anti-inflammation (1)
- Anti-sepsis activity (1)
- Anticancer selectivity (1)
- CAMP‐dependent protein kinase (1)
- CHLOROPEROXIDASE COMPOUND-I; DENSITY-FUNCTIONAL THEORY; INTEGRAL MOLECULAR-DYNAMICS; THEORETICAL PERSPECTIVE; REACTIVE INTERMEDIATE; MAGNETIC-PROPERTIES; QM/MM CALCULATIONS; CYTOCHROME-P450; HYDROXYLATION; CATALASE (1)
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- Dermatan sulfate (1)
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- HINT (1)
- HINT Water-Relevance metric (1)
- Heparan sulfate (1)
- Heparin (1)
- Heparin/heparan sulfate (1)
- Huanglian Jiedu Decoction (1)
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- Keratan sulfate (1)
- Kinetics (1)
- L205R‐PKA (1)
- LPS (1)
- Library screening (1)
- Lipid A (1)
- Liver cancer (1)
- Mimetics (1)
- Molecular docking (1)
- NeuroAIDS; Bivalent ligands; GPCR dimerization; Structure-activity relationship; HUMAN-IMMUNODEFICIENCY-VIRUS; MOLECULAR-DYNAMICS SIMULATIONS; MACROPHAGE-TROPIC HIV-1; CENTRAL-NERVOUS-SYSTEM; IN-VITRO; MARAVIROC UK-427 (1)
Articles 1 - 25 of 25
Full-Text Articles in Medicine and Health Sciences
Glycosaminoglycans And Glycosaminoglycan Mimetics In Cancer And Inflammation, Shravan Morla
Glycosaminoglycans And Glycosaminoglycan Mimetics In Cancer And Inflammation, Shravan Morla
Medicinal Chemistry Publications
Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer’s disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed …
Kinetics And Inhibition Studies Of The L205r Mutant Of Camp-Dependent Protein Kinase Involved In Cushing’S Syndrome, Nicole M. Luzi, Charles E. Lyons, Darrell L. Peterson, Keith C. Ellis
Kinetics And Inhibition Studies Of The L205r Mutant Of Camp-Dependent Protein Kinase Involved In Cushing’S Syndrome, Nicole M. Luzi, Charles E. Lyons, Darrell L. Peterson, Keith C. Ellis
Medicinal Chemistry Publications
Overproduction of cortisol by the hypothalamus–pituitary–adrenal hormone system results in the clinical disorder known as Cushing's syndrome. Genomics studies have identified a key mutation (L205R) in the α‐isoform of the catalytic subunit of cAMP‐dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone‐independent Cushing's syndrome. Here, we conducted kinetics and inhibition studies on the L205R‐PKACα mutant. We have found that the L205R mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (kcat/KM) for each substrate by 12‐fold and 4.5‐fold, respectively. We have also determined the IC …
The Anti-Sepsis Activity Of The Components Of Huanglian Jiedu Decoction With High Lipid A-Binding Affinity, Guirong Chen, Yubin Xu, Jing Jing, Brianna Mackie, Xinchuan Zheng, Xu Zhang, Jing Wang, Xuetao Li
The Anti-Sepsis Activity Of The Components Of Huanglian Jiedu Decoction With High Lipid A-Binding Affinity, Guirong Chen, Yubin Xu, Jing Jing, Brianna Mackie, Xinchuan Zheng, Xu Zhang, Jing Wang, Xuetao Li
Medicinal Chemistry Publications
Huanglian Jiedu Decoction (HJD), one of the classic recipes for relieving toxicity and fever, is a common method for treating sepsis in China. However, the effective components of HJD have not yet been identified. This experiment was carried out to elucidate the effective components of HJD against sepsis. Thus, seven fractions from HJD were tested using a biosensor to test their affinity for lipid A. The components obtained that had high lipid A-binding fractions were further separated, and their affinities to lipid A were assessed with the aid of a biosensor. The levels of LPS in the blood were measured, …
Metabolism And Metabolic Inhibition Of Xanthotoxol In Human Liver Microsomes, Zhongnv Ma, Xianbao Shi, Gang Zhang, Feng Guo, Lina Shan, Jiqun Cai
Metabolism And Metabolic Inhibition Of Xanthotoxol In Human Liver Microsomes, Zhongnv Ma, Xianbao Shi, Gang Zhang, Feng Guo, Lina Shan, Jiqun Cai
Medicinal Chemistry Publications
Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 …
Metabolism And Metabolic Inhibition Of Xanthotoxol In Human Liver Microsomes, Zhongnv Ma, Xianbao Shi, Gang Zhang, Feng Guo, Lina Shan, Jiqun Cai
Metabolism And Metabolic Inhibition Of Xanthotoxol In Human Liver Microsomes, Zhongnv Ma, Xianbao Shi, Gang Zhang, Feng Guo, Lina Shan, Jiqun Cai
Medicinal Chemistry Publications
Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 …
Exploration Of Bivalent Ligands Targeting Putative Mu Opioid Receptor And Chemokine Receptor Ccr5 Dimerization, Christopher K. Arnatt, Bethany A. Falls, Yunyun Yuan, Thomas J. Raborg, Ruturaj R. Masvekar, Nazira El-Hage, Dana E. Selley, Anthony V. Nicola, Pamela E. Knapp, Kurt F. Hauser, Yan Zhang
Exploration Of Bivalent Ligands Targeting Putative Mu Opioid Receptor And Chemokine Receptor Ccr5 Dimerization, Christopher K. Arnatt, Bethany A. Falls, Yunyun Yuan, Thomas J. Raborg, Ruturaj R. Masvekar, Nazira El-Hage, Dana E. Selley, Anthony V. Nicola, Pamela E. Knapp, Kurt F. Hauser, Yan Zhang
Medicinal Chemistry Publications
Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized …
Allosteric Inhibition Of Factor Xiiia. Non-Saccharide Glycosaminoglycan Mimetics, But Not Glycosaminoglycans, Exhibit Promising Inhibition Profile, Rami A. Al-Horani, Rajesh Karuturi, Michael Lee, Daniel K. Afosa, Umesh R. Desai
Allosteric Inhibition Of Factor Xiiia. Non-Saccharide Glycosaminoglycan Mimetics, But Not Glycosaminoglycans, Exhibit Promising Inhibition Profile, Rami A. Al-Horani, Rajesh Karuturi, Michael Lee, Daniel K. Afosa, Umesh R. Desai
Medicinal Chemistry Publications
Factor XIIIa (FXIIIa) is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa’s active site by using sulfated glycosaminoglycans (GAGs) or non-saccharide GAG mimetics (NSGMs) would lead to the discovery of the first allosteric …
Anticancer Activity Of A Thymidine Quinoxaline Conjugate Is Modulated By Cytosolic Thymidine Pathways, Qiong Wei, Haijuan Liu, Honghao Zhou, Dejun Zhang, Zhiwei Zhang, Qibing Zhou
Anticancer Activity Of A Thymidine Quinoxaline Conjugate Is Modulated By Cytosolic Thymidine Pathways, Qiong Wei, Haijuan Liu, Honghao Zhou, Dejun Zhang, Zhiwei Zhang, Qibing Zhou
Medicinal Chemistry Publications
Background
High levels of thymidine kinase 1 (TK1) and thymidine phosphorylase (TYMP) are key molecular targets by thymidine therapeutics in cancer treatment. The dual roles of TYMP as a tumor growth factor and a key activation enzyme of anticancer metabolites resulted in a mixed outcome in cancer patients. In this study, we investigated the roles of TK1 and TYMP on a thymidine quinoxaline conjugate to evaluate an alternative to circumvent the contradictive role of TYMP.
Methods
TK1 and TYMP levels in multiple liver cell lines were assessed along with the cytotoxicity of the thymidine conjugate. Cellular accumulation of the thymidine …
6-Hydroxyflavone And Derivatives Exhibit Potent Anti-Inflammatory Activity Among Mono-, Di- And Polyhydroxylated Flavones In Kidney Mesangial Cells, Xing Wang, Zhiwei Wang, Preetpal Singh Sidhu, Umesh R. Desai, Qibing Zhou
6-Hydroxyflavone And Derivatives Exhibit Potent Anti-Inflammatory Activity Among Mono-, Di- And Polyhydroxylated Flavones In Kidney Mesangial Cells, Xing Wang, Zhiwei Wang, Preetpal Singh Sidhu, Umesh R. Desai, Qibing Zhou
Medicinal Chemistry Publications
Inflammatory responses by kidney mesangial cells play a critical role in the glomerulonephritis. The anti-inflammatory potential of nineteen mono-, di- and polyhydroxylated flavones including fisetin, quercetin, morin, tricetin, gossypetin, apigenin and myricetin were investigated on rat mesangial cells with lipopolysaccharide (LPS) as the inflammatory stimuli. 6-Hydroxyflavone and 4′,6-dihydroxyflavone exhibited high activity with IC50 in the range of 2.0 μM, a much better inhibition potential in comparison to the well-studied polyhydroxylated flavones. Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals. Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6-methoxyflavone was the …
Plasmin Regulation Through Allosteric, Sulfated, Small Molecules, Rami A. Al-Horani, Rajesh Karuturi, Domonique T. White, Umesh R. Desai
Plasmin Regulation Through Allosteric, Sulfated, Small Molecules, Rami A. Al-Horani, Rajesh Karuturi, Domonique T. White, Umesh R. Desai
Medicinal Chemistry Publications
Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed …
Structural Studies Of Aav2 Rep68 Reveal A Partially Structured Linker And Compact Domain Conformation, Faik N. Musayev, Francisco Zarate-Perez, Martino Bardelli, Clayton Bishop, Emil F. Saniev, R. Michael Linden, Els Henckaerts, Carlos R. Escalante
Structural Studies Of Aav2 Rep68 Reveal A Partially Structured Linker And Compact Domain Conformation, Faik N. Musayev, Francisco Zarate-Perez, Martino Bardelli, Clayton Bishop, Emil F. Saniev, R. Michael Linden, Els Henckaerts, Carlos R. Escalante
Medicinal Chemistry Publications
Adeno-associated virus (AAV) nonstructural proteins Rep78 and Rep68 carry out all DNA transactions that regulate the AAV life cycle. They share two multifunctional domains: an N-terminal origin binding/nicking domain (OBD) from the HUH superfamily and a SF3 helicase domain. A short linker of ~20 amino acids that is critical for oligomerization and function connects the two domains. Although X-ray structures of the AAV5 OBD and AAV2 helicase domains have been determined, information about the full-length protein and linker conformation is not known. This article presents the solution structure of AAV2 Rep68 using small-angle X-ray scattering (SAXS). We first determined the …
A Simple Method For Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation Of Key Principles From Heparin/Heparan Sulfate-Binding Proteins, Aurijit Sarkar, Umesh R. Desai
A Simple Method For Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation Of Key Principles From Heparin/Heparan Sulfate-Binding Proteins, Aurijit Sarkar, Umesh R. Desai
Medicinal Chemistry Publications
Glycosaminoglycans (GAGs) affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS) on proteins that in turn helps predict high specific GAG–protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an …
Toward A Robust Computational Screening Strategy For Identifying Glycosaminoglycan Sequences That Display High Specificity For Target Proteins, Nehru Viji Sankaranarayanan, Umesh R. Desai
Toward A Robust Computational Screening Strategy For Identifying Glycosaminoglycan Sequences That Display High Specificity For Target Proteins, Nehru Viji Sankaranarayanan, Umesh R. Desai
Medicinal Chemistry Publications
Glycosaminoglycans (GAGs) interact with many proteins to regulate processes such as hemostasis, cell adhesion, growth and differentiation and viral infection. Yet, majority of these interactions remain poorly understood at a molecular level. A major reason for this state is the phenomenal structural diversity of GAGs, which has precluded analysis of specificity of their interactions. We had earlier presented a computational protocol for predicting “high-specificity” GAG sequences based on combinatorial virtual library screening (CVLS) technology. In this work, we expand the robustness of this technology through rigorous studies of parameters affecting GAG recognition of proteins, especially antithrombin and thrombin. The CVLS …
Intuitive, But Not Simple: Including Explicit Water Molecules In Protein-Protein Docking Simulations Improves Model Quality, Hardik I. Parikh, Glen E. Kellogg
Intuitive, But Not Simple: Including Explicit Water Molecules In Protein-Protein Docking Simulations Improves Model Quality, Hardik I. Parikh, Glen E. Kellogg
Medicinal Chemistry Publications
Characterizing the nature of interaction between proteins that have not been experimentally co-crystallized requires a computational docking approach that can successfully predict the spatial conformation adopted in the complex. In this work, the Hydropathic INTeractions (HINT) force field model was used for scoring docked models in a data set of 30 high-resolution crystallographically characterized “dry” protein-protein complexes, and was shown to reliably identify native-like models. However, most current protein-protein docking algorithms fail to explicitly account for water molecules involved in bridging interactions that mediate and stabilize the association of the protein partners, so we used HINT to illuminate the physical …
Crystal Structures Of Influenza A Virus Matrix Protein M1: Variations On A Theme, Martin K. Safo, Faik N. Musayev, Philip D. Mosier, Qibing Zhou, Hang Xie, Umesh R. Desai
Crystal Structures Of Influenza A Virus Matrix Protein M1: Variations On A Theme, Martin K. Safo, Faik N. Musayev, Philip D. Mosier, Qibing Zhou, Hang Xie, Umesh R. Desai
Medicinal Chemistry Publications
Matrix protein 1 (M1) of the influenza A virus plays multiple roles in virion assembly and infection. Interest in the pH dependence of M1's multiple functions led us to study the effect of subtle pH changes on M1 structure, resulting in the elucidation of a unique low-pH crystal structure of the N1-165-domain of A/WSN/33 (H1N1) M1 that has never been reported. Although the 2.2 Å crystal structure of M1 N-terminus shows a dimer with the two monomers interacting in a face-to-face fashion at low pH as observed earlier, a 44° rotation of the second monomer has led to a significantly …
Biological Characterization Of 3-(2-Amino-Ethyl)-5-[3-(4-Butoxyl-Phenyl)-Propylidene]-Thiazolidine-2,4-Dione (K145) As A Selective Sphingosine Kinase-2 Inhibitor And Anticancer Agent, Kai Liu, Tai L. Guo, Nitai C. Hait, Jeremy Allegood, Hardik I. Parikh, Wenfang Xu, Glen E. Kellogg, Steven Grant, Sarah Spiegel, Shijun Zhang
Biological Characterization Of 3-(2-Amino-Ethyl)-5-[3-(4-Butoxyl-Phenyl)-Propylidene]-Thiazolidine-2,4-Dione (K145) As A Selective Sphingosine Kinase-2 Inhibitor And Anticancer Agent, Kai Liu, Tai L. Guo, Nitai C. Hait, Jeremy Allegood, Hardik I. Parikh, Wenfang Xu, Glen E. Kellogg, Steven Grant, Sarah Spiegel, Shijun Zhang
Medicinal Chemistry Publications
In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione(K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly …
Isozyme-Specific Ligands For O-Acetylserine Sulfhydrylase, A Novel Antibiotic Target, Francesca Spyrakis, Ratna Singh, Pietro Cozzini, Enea Salsi, Paolo Felici, Samanta Raboni, Paolo Benedetti, Gabriele Cruciani, Glen E. Kellogg, Paul F. Cook, Andrea Mozzarelli
Isozyme-Specific Ligands For O-Acetylserine Sulfhydrylase, A Novel Antibiotic Target, Francesca Spyrakis, Ratna Singh, Pietro Cozzini, Enea Salsi, Paolo Felici, Samanta Raboni, Paolo Benedetti, Gabriele Cruciani, Glen E. Kellogg, Paul F. Cook, Andrea Mozzarelli
Medicinal Chemistry Publications
The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O-acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lackO-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two …
Cyanine 5.5 Conjugated Nanobubbles As A Tumor Selective Contrast Agent For Dual Ultrasound-Fluorescence Imaging In A Mouse Model, Liyi Mai, Anna Yao, Jing Li, Qiong Wei, Ming Yuchi, Xiaoling He, Mingyue Ding, Qibing Zhou
Cyanine 5.5 Conjugated Nanobubbles As A Tumor Selective Contrast Agent For Dual Ultrasound-Fluorescence Imaging In A Mouse Model, Liyi Mai, Anna Yao, Jing Li, Qiong Wei, Ming Yuchi, Xiaoling He, Mingyue Ding, Qibing Zhou
Medicinal Chemistry Publications
Nanobubbles and microbubbles are non-invasive ultrasound imaging contrast agents that may potentially enhance diagnosis of tumors. However, to date, both nanobubbles and microbubbles display poor in vivo tumor-selectivity over non-targeted organs such as liver. We report here cyanine 5.5 conjugated nanobubbles (cy5.5-nanobubbles) of a biocompatible chitosan–vitamin C lipid system as a dual ultrasound-fluorescence contrast agent that achieved tumor-selective imaging in a mouse tumor model. Cy5.5-nanobubble suspension contained single bubble spheres and clusters of bubble spheres with the size ranging between 400–800 nm. In the in vivo mouse study, enhancement of ultrasound signals at tumor site was found to persist over …
A Gga Plus U Approach To Effective Electronic Correlations In Thiolate-Ligated Iron-Oxo (Iv) Porphyrin, Justin Elenewski, John C. Hackett
A Gga Plus U Approach To Effective Electronic Correlations In Thiolate-Ligated Iron-Oxo (Iv) Porphyrin, Justin Elenewski, John C. Hackett
Medicinal Chemistry Publications
High-valent oxo-metal complexes exhibit correlated electronic behavior on dense, low-lying electronic state manifolds, presenting challenging systems for electronic structure methods. Among these species, the iron-oxo (IV) porphyrin denoted Compound I occupies a privileged position, serving a broad spectrum of catalytic roles. The most reactive members of this family bear a thiolate axial ligand, exhibiting high activity toward molecular oxygen activation and substrate oxidation. The default approach to such systems has entailed the use of hybrid density functionals or multi-configurational/multireference methods to treat electronic correlation. An alternative approach is presented based on the GGA+U approximation to density functional theory, in …
On The Specificity Of Heparin/Heparan Sulfate Binding To Proteins. Anion-Binding Sites On Antithrombin And Thrombin Are Fundamentally Different, Philip D. Mosier, Chandravel Krishnasamy, Glen E. Kellogg, Umesh R. Desai
On The Specificity Of Heparin/Heparan Sulfate Binding To Proteins. Anion-Binding Sites On Antithrombin And Thrombin Are Fundamentally Different, Philip D. Mosier, Chandravel Krishnasamy, Glen E. Kellogg, Umesh R. Desai
Medicinal Chemistry Publications
Background
The antithrombin–heparin/heparan sulfate (H/HS) and thrombin–H/HS interactions are recognized as prototypic specific and non-specific glycosaminoglycan (GAG)–protein interactions, respectively. The fundamental structural basis for the origin of specificity, or lack thereof, in these interactions remains unclear. The availability of multiple co-crystal structures facilitates a structural analysis that challenges the long-held belief that the GAG binding sites in antithrombin and thrombin are essentially similar with high solvent exposure and shallow surface characteristics.
Methodology
Analyses of solvent accessibility and exposed surface areas, gyrational mobility, symmetry, cavity shape/size, conserved water molecules and crystallographic parameters were performed for 12 X-ray structures, which include 12 …
Pyridoxal 5′-Phosphate Is A Slow Tight Binding Inhibitor Of E. Coli Pyridoxal Kinase, Mohini S. Ghatge, Roberto Contestabile, Martino L. Di Salvo, Jigar V. Desai, Amit Gandhi, Christina M. Camara, Rita Florio, Isabel N. Gonzalez, Alessia Parroni, Verne Schirch, Martin A. Safo
Pyridoxal 5′-Phosphate Is A Slow Tight Binding Inhibitor Of E. Coli Pyridoxal Kinase, Mohini S. Ghatge, Roberto Contestabile, Martino L. Di Salvo, Jigar V. Desai, Amit Gandhi, Christina M. Camara, Rita Florio, Isabel N. Gonzalez, Alessia Parroni, Verne Schirch, Martin A. Safo
Medicinal Chemistry Publications
Pyridoxal 5′-phosphate (PLP) is a cofactor for dozens of B6 requiring enzymes. PLP reacts with apo-B6 enzymes by forming an aldimine linkage with the ε-amino group of an active site lysine residue, thus yielding the catalytically active holo-B6 enzyme. During protein turnover, the PLP is salvaged by first converting it to pyridoxal by a phosphatase and then back to PLP by pyridoxal kinase. Nonetheless, PLP poses a potential toxicity problem for the cell since its reactive 4′-aldehyde moiety forms covalent adducts with other compounds and non-B6 proteins containing thiol or amino groups. The regulation of PLP homeostasis in the cell …
Crystal Structures Of Human Pyridoxal Kinase In Complex With The Neurotoxins, Ginkgotoxin And Theophylline: Insights Into Pyridoxal Kinase Inhibition, Amit Gandhi, Jigar V. Desai, Mohini S. Ghatge, Martino L. Di Salvo, Stefano Di Biase, Richmond Danso-Danquah, Faik N. Musayev, Roberto Contestabile, Verne Schirch, Martin A. Safo
Crystal Structures Of Human Pyridoxal Kinase In Complex With The Neurotoxins, Ginkgotoxin And Theophylline: Insights Into Pyridoxal Kinase Inhibition, Amit Gandhi, Jigar V. Desai, Mohini S. Ghatge, Martino L. Di Salvo, Stefano Di Biase, Richmond Danso-Danquah, Faik N. Musayev, Roberto Contestabile, Verne Schirch, Martin A. Safo
Medicinal Chemistry Publications
Several drugs and natural compounds are known to be highly neurotoxic, triggering epileptic convulsions or seizures, and causing headaches, agitations, as well as other neuronal symptoms. The neurotoxic effects of some of these compounds, including theophylline and ginkgotoxin, have been traced to their inhibitory activity against human pyridoxal kinase (hPL kinase), resulting in deficiency of the active cofactor form of vitamin B6, pyridoxal 5′-phosphate (PLP). Pyridoxal (PL), an inactive form of vitamin B6 is converted to PLP by PL kinase. PLP is the B6 vitamer required as a cofactor for over 160 enzymatic activities essential in primary and secondary metabolism. …
Design, Synthesis, And In Vitro And In Vivo Biological Studies Of A 3′-Deoxythymidine Conjugate That Potentially Kills Cancer Cells Selectively, Qiong Wei, Dejun Zhang, Anna Yao, Liyi Mai, Zhiwei Zhang, Qibing Zhou
Design, Synthesis, And In Vitro And In Vivo Biological Studies Of A 3′-Deoxythymidine Conjugate That Potentially Kills Cancer Cells Selectively, Qiong Wei, Dejun Zhang, Anna Yao, Liyi Mai, Zhiwei Zhang, Qibing Zhou
Medicinal Chemistry Publications
Thymidine kinases (TKs) have been considered one of the potential targets for anticancer therapeutic because of their elevated expressions in cancer cells. However, nucleobase analogs targeting TKs have shown poor selective cytotoxicity in cancer cells despite effective antiviral activity. 3′-Deoxythymidine phenylquinoxaline conjugate (dT-QX) was designed as a novel nucleobase analog to target TKs in cancer cells and block cell replication via conjugated DNA intercalating quinoxaline moiety. In vitro cell screening showed that dT-QX selectively kills a variety of cancer cells including liver carcinoma, breast adenocarcinoma and brain glioma cells; whereas it had a low cytotoxicity in normal cells such as …
Applying An Empirical Hydropathic Forcefield In Refinement May Improve Low-Resolution Protein X-Ray Crystal Structures, Vishal N. Koparde, J. Neel Scarsdale, Glen E. Kellogg
Applying An Empirical Hydropathic Forcefield In Refinement May Improve Low-Resolution Protein X-Ray Crystal Structures, Vishal N. Koparde, J. Neel Scarsdale, Glen E. Kellogg
Medicinal Chemistry Publications
Background
The quality of X-ray crystallographic models for biomacromolecules refined from data obtained at high-resolution is assured by the data itself. However, at low-resolution, >3.0 Å, additional information is supplied by a forcefield coupled with an associated refinement protocol. These resulting structures are often of lower quality and thus unsuitable for downstream activities like structure-based drug discovery.
Methodology
An X-ray crystallography refinement protocol that enhances standard methodology by incorporating energy terms from the HINT (Hydropathic INTeractions) empirical forcefield is described. This protocol was tested by refining synthetic low-resolution structural data derived from 25 diverse high-resolution structures, and referencing the resulting …
Bound Water At Protein-Protein Interfaces: Partners, Roles And Hydrophobic Bubbles As A Conserved Motif, Mostafa H. Ahmed, Francesca Spyrakis, Pietro Cozzini, Parijat K. Tripathi, Andrea Mozzarelli, J. Neel Scarsdale, Martin A. Safo, Glen E. Kellogg
Bound Water At Protein-Protein Interfaces: Partners, Roles And Hydrophobic Bubbles As A Conserved Motif, Mostafa H. Ahmed, Francesca Spyrakis, Pietro Cozzini, Parijat K. Tripathi, Andrea Mozzarelli, J. Neel Scarsdale, Martin A. Safo, Glen E. Kellogg
Medicinal Chemistry Publications
Background
There is a great interest in understanding and exploiting protein-protein associations as new routes for treating human disease. However, these associations are difficult to structurally characterize or model although the number of X-ray structures for protein-protein complexes is expanding. One feature of these complexes that has received little attention is the role of water molecules in the interfacial region.
Methodology
A data set of 4741 water molecules abstracted from 179 high-resolution (≤ 2.30 Å) X-ray crystal structures of protein-protein complexes was analyzed with a suite of modeling tools based on the HINT forcefield and hydrogen-bonding geometry. A metric termed …