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Rampogu, Shailima,Parate, Shraddha,Parameswaran, Saravanan,Park, Chanin,Baek, Ayoung,Son, Minky,Park, Yohan,Park, Seok Ju,Lee, Keun Woo Elsevier 2019 Computational biology and chemistry Vol.83 No.-
<P><B>Abstract</B></P> <P>Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present <I>in silico</I> investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski’s rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds – Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Natural compounds are identified as Hsp90 inhibitors. </LI> <LI> These compounds show stable interactions with key residues. </LI> <LI> Non-quinone containing compounds were discovered by structure based pharmacophore modelling. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria
Rampogu, Shailima,Baek, Ayoung,Son, Minky,Zeb, Amir,Park, Chanin,Kumar, Raj,Lee, Gihwan,Kim, Donghwan,Choi, Yeonuk,Cho, Yeongrae,Park, Yohan,Park, Seok Ju,Lee, Keun Woo Hindawi 2017 BioMed research international Vol.2017 No.-
<P>Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski's rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.</P>
Pharmacophore Identification for Peroxisome Proliferator-Activated Receptor Gamma Agonists
손영식,이윤호,Chanin Park,Swan Hwang,Songmi Kim,Ayoung Baek,Minky Son,서정근,Hyong-Ha Kim,이근우 대한화학회 2011 Bulletin of the Korean Chemical Society Vol.32 No.1
Peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors and their activation induces regulation of fatty acid storage and glucose metabolism. Therefore, the PPARγ is a major target for the treatment of type 2 diabetes mellitus. In order to generate pharmacophore model, 1080 known agonists database was constructed and a training set was selected. The Hypo7, selected from 10 hypotheses, contains four features: three hydrogen-bond acceptors (HBA) and one general hydrophobic (HY). This pharmacophore model was validated by using 862 test set compounds with a correlation coefficient of 0.903 between actual and estimated activity. Secondly, CatScramble method was used to verify the model. Hence, the validated Hypo7 was utilized for searching new lead compounds over 238,819 and 54,620 chemical structures in NCI and Maybridge database, respectively. Then the leads were selected by screening based on the pharmacophore model, predictive activity, and Lipinski’s rules. Candidates were obtained and subsequently the binding affinities to PPARγ were investigated by the molecular docking simulations. Finally the best two compounds were presented and would be useful to treat type 2 diabetes.
Sakkiah, Sugunadevi,Thangapandian, Sundarapandian,Park, Chanin,Son, Minky,Lee, Keun W. Blackwell Publishing Ltd 2012 Chemical biology & drug design Vol.80 No.2
<P>Sirtuin, NAD<SUP>+</SUP>‐dependent histone deacetylase enzyme, emerged as a potential therapeutic target, and modulations by small molecules could be effective drugs for various diseases. Owing to the absence of complex structure of sirtuin 2 (SIRT2), sirtinol was docked in the NAD<SUP>+</SUP> binding site and subjected to 5‐nseconds molecular dynamics (MD) simulation. LigandScout was used to develop hypotheses based on 3‐representative SIRT2 complex structures from MD. Three structure‐based hypotheses are generated and merged to form dynamics hypothesis. The dynamics hypothesis was validated using test and decoy sets. The results showed that dynamic hypothesis represents the complementary features of SIRT2 active site. Dynamic hypothesis was used to screen ChemDiv database, and hits were filtered through ADMET, rule of five, and two different molecular docking studies. Finally, 21 molecules were selected as potent leads based on consensus score from LigandFit, Gold fitness score, binding affinity from VINA as well as based on the important interactions with critical residues in SIRT2 active site. Hence, we suggest that the dynamic hypothesis will be reliable in the identification of SIRT2 new lead as well as to reduce time and cost in the drug discovery process.</P>
Rampogu, Shailima,Son, Minky,Park, Chanin,Kim, Hyong-Ha,Suh, Jung-Keun,Lee, Keun Woo Hindawi 2017 BioMed research international Vol.2017 No.-
<P>Breast cancer is one of the leading causes of death noticed in women across the world. Of late the most successful treatments rendered are the use of aromatase inhibitors (AIs). In the current study, a two-way approach for the identification of novel leads has been adapted. 81 chemical compounds were assessed to understand their potentiality against aromatase along with the four known drugs. Docking was performed employing the CDOCKER protocol available on the Discovery Studio (DS v4.5). Exemestane has displayed a higher dock score among the known drug candidates and is labeled as reference. Out of 81 ligands 14 have exhibited higher dock scores than the reference. In the second approach, these 14 compounds were utilized for the generation of the pharmacophore. The validated four-featured pharmacophore was then allowed to screen Chembridge database and the potential Hits were obtained after subjecting them to Lipinski's rule of five and the ADMET properties. Subsequently, the acquired 3,050 Hits were escalated to molecular docking utilizing GOLD v5.0. Finally, the obtained Hits were consequently represented to be ideal lead candidates that were escalated to the MD simulations and binding free energy calculations. Additionally, the gene-disease association was performed to delineate the associated disease caused by CYP19A1.</P>
Tan, Xuefei,Song, Yeong Hun,Park, Chanin,Lee, Ki-Won,Kim, Jeong Yoon,Kim, Dae Wook,Kim, Kwang Dong,Lee, Keun Woo,Curtis-Long, Marcus J.,Park, Ki Hun Pergamon 2016 Bioorganic & medicinal chemistry Vol.24 No.2
<P>Tyrosinase inhibition may be a means to alleviate not only skin hyperpigmentation but also neurodegeneration associated with Parkinson's disease. In the course of metabolite analysis from tyrosinase inhibitory methanol extract (80% inhibition at 20 mu g/ml) of Campylotropis hirtella, we isolated fourteen phenolic compounds, among which neorauflavane 3 emerged as a lead structure for tyrosinase inhibition. Neorauflavane 3 inhibited tyrosinase monophenolase activity with an IC50 of 30 nM. Thus this compound is 400-fold more active than kojic acid. It also inhibited diphenolase (IC50 = 500 nM), significantly. Another potent inhibitor 1 (IC50 = 2.9 mu M) was found to be the most abundant metabolite in C. hirtella. In kinetic studies, compounds 3 showed competitive inhibitory behavior against both monophenolase and diphenolase. It manifested simple reversible slow-binding inhibition against monophenolase with the following kinetic parameters: K-i(app) = 1.48 nM, k(3) = 0.0033 nM (1) min (1) and k(4) = 0.0049 min (1). Neorauflavane 3 efficiently reduced melanin content in B16 melanoma cells with 12.95 mu M of IC50. To develop a pharmacophore model, we explored the binding mode of neuroflavane 3 in the active site of tyrosinase. Docking results show that resorcinol motif of B-ring and methoxy group in A-ring play crucial roles in the binding the enzyme. (C) 2015 Elsevier Ltd. All rights reserved.</P>
Nagakumar Bharatham,Kavitha Bharatham,이윤호,Songmi Kim,Prettina Lazar,Ayoung Baek,Chanin Park,엄희성,하현준,Sae Young Yun,이원구,Sunghoon Kim,이근우 대한화학회 2010 Bulletin of the Korean Chemical Society Vol.31 No.3
Aminoacyl-tRNA synthetases (aaRSs) play vital roles in protein biosynthesis of living organisms and are interesting antibacterial drug targets. In order to find out new inhibitor candidate molecules as antibacterial agent, the binding modes of the candidate molecules were investigated at the active sites of aaRSs by molecular docking study. The docking simulations were performed with 48 compounds from four different scaffolds into the eight different aaRSs. The results show that scaffolds 3 and 4 compounds have consistently better binding capabilities, specifically for HisRS (E. coli) and IleRS (S. aureus). The binding modes of the best compounds with the proteins were well compatible with those of two ligands in crystal structures. Therefore, we expect that the final compounds we present may have reasonable aaRS inhibitory activity.
Kumar, Raj,Son, Minky,Bavi, Rohit,Lee, Yuno,Park, Chanin,Arulalapperumal, Venkatesh,Cao, Guang Ping,Kim, Hyong-ha,Suh, Jung-keun,Kim, Yong-seong,Kwon, Yong Jung,Lee, Keun Woo Springer Science and Business Media LLC 2015 Acta pharmacologica Sinica. Vol.36 No.8
<P>Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches.</P>