Computer aided Molecular Modeling Research Center

Kōbe-shi, Japan

Computer aided Molecular Modeling Research Center

Kōbe-shi, Japan
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Gohda K.,Computer Aided Molecular Modeling Research Center | Teno N.,Hiroshima International University | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University
Journal of Enzyme Inhibition and Medicinal Chemistry | Year: 2012

Plasmin plays important roles in various physiological systems. The identification of inhibitors controlling its regulation represents a promising drug-discovery challenge. To develop selective inhibitors of plasmin, structural information of the binding modes is crucial. Here, a computational docking study was conducted to provide structural insight into plasmin subsite interactions with substrates/inhibitors. Predicted binding modes of two peptide-substrates (D/L-Ile-Phe-Lys), and potent and weak inhibitors (YO-2 and PKSI-527) suggested non-prime and prime subsite interactions relevant to recognition by plasmin. Predicted binding modes also correlated well with the experimental structureactivity relationships for plasmin substrates/inhibitors, namely the differences of KM values between the D- and L-peptide-substrates and inhibitory potencies of YO-2 and PKSI-527. In particular, interaction observed at a hydrophobic pocket near S2 and at a tunnel-shaped hydrophobic S1′ was strongly suggested to be significantly involved in tight binding of inhibitors to plasmin. Our present findings may aid in the design of potent and selective plasmin inhibitors. © 2012 Informa UK, Ltd.


Teno N.,Hiroshima International University | Iguchi Y.,Hiroshima International University | Yamashita Y.,Hiroshima International University | Mori N.,Hiroshima International University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2017

We describe here a novel chemotype with substituted benzimidazole scaffold for nonsteroidal farnesoid X receptor (FXR) antagonists starting from the identification of a screening hit, BB-4. Structure diversity in four regions A-D of BB-4 or 1 is discussed. In particular, regions A and C had an effect on an antagonism against FXR as demonstrated by the derivatives represented by 7 and 15, respectively. Thus, compound 19 arising from the combination of regions A and C underscored an important fact on antagonism against FXR, also showing the reduced small heterodimer partner and the increased cholesterol 7α-hydroxylase expression levels. © 2017 Elsevier Ltd


Teno N.,Hiroshima International University | Gohda K.,Computer Aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

In the development of plasmin inhibitors, a novel chemotype, pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is that the interaction between the plasmin inhibitors and key subsites in plasmin can be controlled by a spacer like hydantoin. The application of the novel chemotype is demonstrated by 1n and provides further evidence on the importance of hydantoin as the spacer. © 2014 Elsevier Ltd. All rights reserved.


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Sueda T.,Hiroshima International University | Tsuda Y.,Kobe Gakuin University
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Lysine-nitrile derivatives having a trisubstituted benzene, which belongs to a new chemical class, were prepared and tested for inhibitory activities against plasmin and the highly homologous plasma kallikrein and urokinase. The use of the novel chemotype in the development of plasmin inhibitors has been demonstrated by derivatives of compound 9. © 2011 Elsevier Ltd. All rights reserved.


Teno N.,Hiroshima International University | Otsubo T.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | And 4 more authors.
Journal of Peptide Science | Year: 2012

Plasmin is best known as the key molecule in the fibrinolytic system, which is critical for clot lysis and can initiate matrix metalloproteinase (MMP) activation cascade. Along with MMP, plasmin is suggested to be involved in physiological processes that are linked to the risk of carcinoma formation. Plasmin inhibitors could be perceived as a promising new principle in the treatment of diseases triggered by plasmin. On the basis of the peptidic sequence derived from the synthetic plasmin substrate, a series of peptidic plasmin inhibitors possessing nitrile as warhead were prepared and evaluated for their inhibitory activities against plasmin and other serine proteases, plasma kallikrein and urokinase. The most potent peptidic inhibitors with the nitrile warhead exhibit the potency toward plasmin (IC50=7.7-11μM) and are characterized by their selectivity profile against plasma kallikrein and urokinase. The results and molecular modeling of the peptidic inhibitor complexed with plasmin reveal that the P2 residue makes favorable contacts with the open binding pocket comprising the S2 and S3 subsites of plasmin. © 2012 European Peptide Society and John Wiley & Sons, Ltd.


Hidaka K.,Kobe Gakuin University | Gohda K.,Computer Aided Molecular Modeling Research Center | Teno N.,Hiroshima International University | Wanaka K.,Research Projects on Thrombosis and Haemostatsis | Tsuda Y.,Kobe Gakuin University
Bioorganic and Medicinal Chemistry | Year: 2016

Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50 = 0.22 and 77 μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site. © 2015 Elsevier Ltd. All rights reserved.


PubMed | Kobe Gakuin University, Kobe Research Projects on Thrombosis and Haemostasis, Hiroshima International University and Computer aided Molecular Modeling Research Center
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016

In this letter we report the design and synthesis of a series of plasmin inhibitors, which share the amino acid-based linker with limited free rotation between the hydantoin moiety and the benzimidazole scaffold. Our studies led to potent plasmin inhibitors and yielded important new insights into their structure-activity relationship for binding to the active site of plasmin.


PubMed | Computer aided Molecular Modeling Research Center
Type: Letter | Journal: Chemical biology & drug design | Year: 2013

We here strove to overcome the limitations of expression analyses such as PCR and IHC, based on molecular recognition between target and probe molecules, by designing synthetic substrates specific to the target molecules to directly estimate the enzymatic functionality in situ. The specific substrate contains a probing unit, which is an organic fragment for specific enzyme binding, and a reactive unit, which is a natural peptide subject to catalysis. In this study, the activation of plasminogen to plasmin was examined in MDA-MB231 breast cancer cells using the plasmin-specific synthetic substrates designed from their inhibitors. The localization and function of the activated plasmin were successfully visualized by fluorophore combined with the specific substrate concurrently. This would be the first time for activated plasmin at work in situ by direct observation. Our concept to directly monitor the functionality of target enzymes can be used straightforwardly for other proteases such as cathepsins or caspases. Also, this substrate concept as a tailor-made substrate would be utilized as a novel functional molecular probe in vivo with appropriate detectable probes.


PubMed | Kobe Gakuin University, Hiroshima International University, Research Projects on Thrombosis and Haemostatsis and Computer Aided Molecular Modeling Research Center
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2016

Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50=0.22 and 77M for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.


PubMed | Kobe Gakuin University, Kobe Research Projects on Thrombosis and Haemostasis, Hiroshima International University and Computer Aided Molecular Modeling Research Center
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2015

Here we report a series of plasmin inhibitors which were originally derived from the parent structure of 1 and 2. Our efforts focused on the optimization of the P4 moiety of 2 and on the quest of alternative scaffold to pyrrolopyrimidine in the parent compounds. The results of the former gave us pivotal information on the further optimization of the P4 moiety in plasmin inhibitors and those of the latter revealed that appropriate moieties extending from the benzimidazole scaffold engaged with S4 pocket in the active site of plasmin.

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