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1.
J Mol Graph Model ; 106: 107914, 2021 07.
Article in English | MEDLINE | ID: mdl-33932736

ABSTRACT

Complement component 3a receptor 1 (C3aR) is an anaphylatoxin receptor that mediates inflammatory processes. Although considerable effort has gone into discovering the antagonists and agonists of C3aR, structural insights are required to search for effective ligands and to elucidate their binding modes and the mechanism of activation and inactivation. No experimental structural data of C3aR have yet been reported. We investigated the binding mode of an antagonist of C3aR using a combination of homology modeling, ligand docking, molecular dynamics simulations, and binding free energy calculations. We produced a plausible binding model consistent with the reported experimental data. We believe that this model is appropriate for the identification of new C3aR antagonists, as it can distinguish between antagonists and decoy compounds.


Subject(s)
Complement C3a , Molecular Dynamics Simulation , Binding Sites , Ligands , Models, Chemical , Molecular Docking Simulation , Protein Binding
2.
J Comput Aided Mol Des ; 35(5): 601-611, 2021 05.
Article in English | MEDLINE | ID: mdl-33635506

ABSTRACT

Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase that is overexpressed in many cancers. Numerous EZH2 inhibitors have been developed as anticancer agents, but recent studies have also focused on protein-protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2 as a novel drug discovery target. Because EED indirectly enhances EZH2 enzymatic activity, EED-EZH2 PPI inhibitors suppress the methyltransferase activity and inhibit cancer growth. By contrast to the numerous promising EZH2 inhibitors, there are a paucity of EED-EZH2 PPI inhibitors reported in the literature. Here, we aimed to discover novel EED-EZH2 PPI inhibitors by first identifying possible binders of EED using an in-house knowledge-based in silico fragment mapping method. Next, 3D pharmacophore models were constructed from the arrangement pattern of the potential binders mapped onto the EED surface. In all, 16 compounds were selected by 3D pharmacophore-based virtual screening followed by docking-based virtual screening. In vitro evaluation revealed that five of these compounds exhibited inhibitory activities. This study has provided structural insights into the discovery and the molecular design of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Polycomb Repressive Complex 2/antagonists & inhibitors , Protein Interaction Maps/drug effects , Computer Simulation , Drug Design , Drug Discovery , Enhancer of Zeste Homolog 2 Protein/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Polycomb Repressive Complex 2/metabolism
3.
Neurosci Res ; 154: 35-44, 2020 May.
Article in English | MEDLINE | ID: mdl-31121203

ABSTRACT

Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, evidence demonstrating the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer's disease is limited. The present study investigated the effect of chlorogenic acids on the prevention of cognitive dysfunction in APP/PS2 transgenic mouse model of Alzheimer's disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was determined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Immunohistochemical analysis revealed that chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid ß (Aß) plaques in the hippocampus. Furthermore, we determined that 5-caffeoylquinic acid, one of the primary coffee polyphenols, did not inhibit Aß fibrillation; however, degraded Aß fibrils. In conclusion, our results demonstrate that coffee polyphenols prevent cognitive deficits and reduce Aß plaque deposition via disaggregation of Aß in the APP/PS2 mouse.


Subject(s)
Alzheimer Disease/prevention & control , Chlorogenic Acid/pharmacology , Coffee/chemistry , Cognitive Dysfunction/prevention & control , Plaque, Amyloid/prevention & control , Polyphenols/pharmacology , Alzheimer Disease/metabolism , Amyloid/drug effects , Amyloid beta-Peptides/metabolism , Animals , Brain/drug effects , Brain/pathology , Cerebral Cortex/drug effects , Chlorogenic Acid/metabolism , Coffee/metabolism , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Male , Memory , Mice , Mice, Transgenic , Morris Water Maze Test/drug effects , Open Field Test/drug effects , Plaque, Amyloid/metabolism , Polyphenols/metabolism , Quinic Acid/analogs & derivatives , Quinic Acid/chemistry , Spatial Learning/drug effects
4.
Yakugaku Zasshi ; 139(5): 827-835, 2019 May 01.
Article in Japanese | MEDLINE | ID: mdl-30842349

ABSTRACT

Proteolysis mediated by the ubiquitin-proteome system plays an important role in cancer. Recently, a deubiquitinating enzyme, ubiquitin-specific protease 7 (USP7) has attracted attention as a key regulator of the p53-human double minute 2 (HDM2) pathway in cancer cells. Although some USP7 enzyme inhibitors have been identified, issues related to activity and selectivity prevent their therapeutic application. In this study, we aimed to search for novel USP7-HDM2 protein-protein interaction (PPI) inhibitors that do not affect the USP7 enzyme activity. Using the fragment-mapping program Fsubsite and the canonical subsite-fragment database (CSFDB) developed in our laboratory, we mapped a variety of fragments onto USP7 protein and constructed 3D-pharmacophore models based on the arrangement patterns of the mapped fragments. Finally, we performed 3D pharmacophore-based virtual screening of a commercial compound database and successfully selected promising USP7-HDM2 PPI inhibitor candidates.


Subject(s)
Antineoplastic Agents , Computer Simulation , Drug Discovery , Protease Inhibitors , Protein Interaction Maps , Proto-Oncogene Proteins c-mdm2 , Restriction Mapping/methods , Ubiquitin-Specific Peptidase 7 , Models, Molecular , Protease Inhibitors/chemistry , Protein Structure, Quaternary , Proteolysis , Proto-Oncogene Proteins c-mdm2/chemistry , Ubiquitin-Specific Peptidase 7/chemistry
5.
Bioorg Med Chem ; 19(20): 5935-47, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21937235

ABSTRACT

Neutral endopeptidase (NEP) plays a key role in the metabolic inactivation of various bioactive peptides such as atrial natriuretic peptide (ANP), endothelins, and enkephalins. Furthermore, NEP is known to work as elastase in skin fibroblast. Therefore, effective inhibitors of NEP offer significant therapeutic interest as antihypertensives, analgesics, and skin anti-aging agents. Recently, the X-ray crystal structure of human NEP complexed with phosphoramidon has been reported and provided insights into the active site specificity of NEP. Here, we designed new inhibitors by using in silico molecular modeling and synthesized them by short steps. Expectedly, we found highly effective inhibitors with sub-nanomolar levels of IC(50) values. These results indicate that our structure-based molecular designing program is useful for obtaining novel NEP inhibitors. Furthermore, these inhibitors may be attractive leads for the generation of new pharmaceuticals for NEP-related diseases.


Subject(s)
Dipeptides/chemistry , Dipeptides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Neprilysin/antagonists & inhibitors , Neprilysin/chemistry , Amino Acid Sequence , Crystallography, X-Ray , Drug Design , Humans , Models, Chemical , Molecular Sequence Data , Molecular Structure , Neprilysin/metabolism , Structure-Activity Relationship
6.
Org Lett ; 12(21): 5068-71, 2010 Nov 05.
Article in English | MEDLINE | ID: mdl-20939604

ABSTRACT

The first total synthesis of incednam (1), the aglycon of antibiotic incednine (2), is described. Incednine has been reported to exhibit significant inhibitory activity against the antiapoptotic oncoproteins Bcl-2 and Bcl-xL. The synthesis of 1 commenced with the preparation of the C1-C13 subunit 3 and the C14-C23 subunit 4. The construction of the novel 24-membered macrocycle was achieved by the application of a Stille coupling between 3 and 4, followed by macrolactamization.


Subject(s)
Disaccharides/chemical synthesis , Lactams/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Molecular Structure
7.
Chem Pharm Bull (Tokyo) ; 56(10): 1470-2, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18827393

ABSTRACT

The binding of amino acids to water-soluble zinc porphyrins in basic aqueous solution was spectrophotometrically analyzed. The amino acids were bound to the porphyrins through the coordination of the N atom with the central zinc ion. Additional attractions arise due to Coulomb interactions between the -COO(-) anion of the amino acids and the -N(CH(3))(3)(+) cation of the porphyrin substituents and due to hydrophobic interactions between the porphyrin plane and the hydrophobic substituents of the amino acids. These attractions could be explained based on the binding data. The compensatory relationships of DeltaS and DeltaH were also discussed.


Subject(s)
Metalloporphyrins/chemistry , Receptors, Amino Acid/chemistry , Amines/chemistry , Kinetics , Magnetic Resonance Spectroscopy , Thermodynamics
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