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RISS 인기검색어
- 검색키워드
- 저자 : Suparna Ghosh (검색결과 5 건)
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Ghosh Suparna,다나싱 이마누엘,류재원,김시욱,이성행 한국미생물·생명공학회 2020 Journal of microbiology and biotechnology Vol.30 No.8
Cytochrome cL (CytcL) is an essential protein in the process of methanol oxidation in methylotrophs. It receives an electron from the pyrroloquinoline quinone (PQQ) cofactor of methanol dehydrogenase (MDH) to produce formaldehyde. The direct electron transfer mechanism between CytcL and MDH remains unknown due to the lack of structural information. To help gain a better understanding of the mechanism, we determined the first crystal structure of heme c containing CytcL from the aquatic methylotrophic bacterium Methylophaga aminisulfidivorans MPT at 2.13 Å resolution. The crystal structure of Ma-CytcL revealed its unique features compared to those of the terrestrial homologues. Apart from Fe in heme, three additional metal ion binding sites for Na+, Ca+, and Fe2+ were found, wherein the ions mostly formed coordination bonds with the amino acid residues on the loop (G93-Y111) that interacts with heme. Therefore, these ions seemed to enhance the stability of heme insertion by increasing the loop's steadiness. The basic N-terminal end, together with helix α4 and loop (G126 to Y136), contributed positive charge to the region. In contrast, the acidic C-terminal end provided a negatively charged surface, yielding several electrostatic contact points with partner proteins for electron transfer. These exceptional features of Ma-CytcL, along with the structural information of MDH, led us to hypothesize the need for an adapter protein bridging MDH to CytcL within appropriate proximity for electron transfer. With this knowledge in mind, the methanol oxidation complex reconstitution in vitro could be utilized to produce metabolic intermediates at the industry level.
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Suparna Ghosh,Seketoulie Keretsu,Seung Joo Cho 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.8
Phosphoinositol-3-kinase ? (PI3K?) is a member of the class-IB PI3K superfamily and plays a significant role in G-protein-coupled receptor mediated cell signaling. Recent studies have suggested that elevated expression of PI3K? in tumor-associated macrophages strongly influences immune suppression and tumor growth. Due to the presence of many isoforms of PI3K, the selective inhibition of PI3K? remains challenging. Therefore, it is necessary to design more potent inhibitors against PI3K? for cancer treatment. In this study, we have reported the critical interactions of isoindolinone-based inhibitors with PI3K? by docking and molecular dynamics simulations. The binding free energy of the receptor-ligand complex was calculated using molecular mechanics/Poison-Boltzmann surface area approach. We have performed the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) to determine the structure?activity relationship of the inhibitors. The CoMFA (q2 = 0.681 and r2 = 0.968) and CoMSIA (q2 = 0.665 and r2 = 0.982) models showed reasonable predictive ability. Thereafter, the contour maps derived from CoMFA and CoMSIA were used to design several new compounds, among which, the compound D04 showed high predicted activity values. The designed compound was subjected to absorption-distribution-metabolism-excretion/toxicity prediction and synthetic accessibility analyses. Our results could provide theoretical guidance for the future development of new PI3K? inhibitors.
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Structure–activity relationship and in silico development of c-Met kinase inhibitors
Ghosh Suparna,Cho Seung Joo 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.6
Overexpression and concomitant drug resistance of c-Met kinase are strongly associated with poor prognosis in gastric carcinoma. This needs the further development of existing lead compounds against c-Met. Herein, we conducted molecular modeling studies of 4-phenoxypyridine derivatives as c-Met kinase inhibitors using docking, molecular dynamics (MD), and binding energy estimation to examine receptor–ligand interaction, complex stability, and binding affinity. We developed statistically significant three-dimensional structure– activity relationship models (3D-QSAR) to correlate the physicochemical characteristics of the inhibitors with their biological activities. The field effects of the chemical descriptors were determined as contour polyhedrons and emphasized as SAR. Thirty new compounds were designed according to the SAR scheme, and their activities were predicted using the 3D-QSAR model. The designed compounds with higher predicted pIC50 values than the most active compounds in the dataset were subjected to absolute binding free-energy evaluation by free energy perturbation (FEP) method.
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Comparative binding affinity analysis of dual CDK2/FLT3 inhibitors
Ghosh Suparna,Cho Seung Joo 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.12
Selective inhibition of cyclin-dependent kinase 2 (CDK2) using small molecules is gaining popularity for the treatment of certain types of acute myeloid leuke- mia (AML). In this study, we used different molecular modeling techniques to investigate the structure–activity relationship (SAR) and binding modalities of dual CDK2/FLT3 inhibitors. The key chemical characteristics of the 3H-pyrazolo [4,3-f]quinoline derivatives were highlighted as descriptive colored contours using comparative molecular similarity analysis (CoMSIA). Modifying chemical groups in existing compounds along these contours could improve CDK2 selec- tivity over FMS-like tyrosine kinase 3 (FLT3). We determined the ligand affinities for CDK2 by estimating the binding free energy using molecular mechanics generalized Born surface area (MM-GBSA) and umbrella sampling (US) simulations. Reasonable correlations were found between the computed and experimental binding energies, suggesting that MM-GBSA and US can be used to reliably predict the binding affinities of new compounds in the more potent CDK2 drug development process.
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3D-QSAR, Docking and Molecular Dynamics Simulation Study of C-Glycosylflavones as GSK-3β Inhibitors
Ghosh, Suparna,Keretsu, Seketoulie,Cho, Seung Joo The Basic Science Institute Chosun University 2020 조선자연과학논문집 Vol.13 No.4
Abnormal regulation, hyperphosphorylation, and aggregation of the tau protein are the hallmark of several types of dementia, including Alzheimer's Disease. Increased activity of Glycogen Synthase Kinase-3β (GSK-3β) in the Central Nervous System (CNS), increased the tau hyperphosphorylation and caused the neurofibrillary tangles (NFTs) formation in the brain cells. Over the last two decades, numerous adenosine triphosphate (ATP) competitive inhibitors have been discovered that show inhibitory activity against GSK-3β. But these compounds exhibited off-target effects which motivated researchers to find new GSK-3β inhibitors. In the present study, we have collected the dataset of 31 C-Glycosylflavones derivatives that showed inhibitory activity against GSK-3β. Among the dataset, the most active compound was docked with the GSK-3β and molecular dynamics (MD) simulation was performed for 50 ns. Based on the 50 ns MD pose of the most active compound, the other dataset compounds were sketched, minimized, and aligned. The 3D-QSAR based Comparative Molecular Field Analysis (CoMFA) model was developed, which showed a reasonable value of q2=0.664 and r2=0.920. The contour maps generated based on the CoMFA model elaborated on the favorable substitutions at the R2 position. This study could assist in the future development of new GSK-3β inhibitors.
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