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Sakkiah, Sugunadevi,Thangapandian, Sundarapandian,Lee, Keun Woo Blackwell Publishing Ltd 2012 Chemical biology & drug design Vol.80 No.1
<P>Cathepsin D is a major component of lysosomes and plays a major role in catabolism and degenerative diseases. The quantitative structure–activity relationship study was used to explore the critical chemical features of cathepsin D inhibitors. Top 10 hypotheses were built based on 36 known cathepsin D inhibitors using H<SMALL>ypo</SMALL>G<SMALL>en</SMALL>/D<SMALL>iscovery</SMALL> S<SMALL>tudio</SMALL> v2.5. The best hypothesis Hypo1 consists of three hydrophobic, one hydrogen bond acceptor lipid, and one hydrogen bond acceptor features. The selected Hypo1 model was cross‐validated using Fischer’s randomization method to identify the strong correlation between experimental and predicted activity value as well as the test set and decoy sets used to validate its predictability. Moreover, the best hypothesis was used as a 3D query in virtual screening of Scaffold database. Subsequently, the screened hit molecules were filtered by applying Lipinski’s rule of five, absorption, distribution, metabolism, and toxicity, and molecular docking studies. Finally, 49 compounds were obtained as potent cathepsin D inhibitors based on the consensus scoring values, critical interactions with protein active site residues, and predicted activity values. Thus, we suggest that the application of Hypo1 could assist in the selection of potent cathepsin D leads from various databases. Hence, this model was used as a valuable tool to design new candidate for cathepsin D inhibitors.</P>
Sakkiah, Sugunadevi,Thangapandian, Sundarapandian,Kim, Yong-Seong,Lee, Keun-Woo Korean Chemical Society 2012 Bulletin of the Korean Chemical Society Vol.33 No.3
Identification of the selective chemical features for Aurora-B inhibitors gained much attraction in drug discovery for the treatment of cancer. Hence to identify the Aurora-B critical features various techniques were utilized such as pharmacophore generation, virtual screening, homology modeling, molecular dynamics, and docking. Top ten hypotheses were generated for Aurora-B and Aurora-A. Among ten hypotheses, HypoB1 and HypoA1 were selected as a best hypothesis for Aurora-B and Aurora-A based on cluster analysis and ranking score, respectively. Test set result revealed that ring aromatic (RA) group in HypoB1 plays an essential role in differentiates Aurora-B from Aurora-A inhibitors. Hence, HypoB1 used as 3D query in virtual screening of databases and the hits were sorted out by applying drug-like properties and molecular docking. The molecular docking result revealed that 15 hits have shown strong hydrogen bond interactions with Ala157, Glu155, and Lys106. Hence, we proposed that HypoB1 might be a reasonable hypothesis to retrieve the structurally diverse and selective leads from various databases to inhibit Aurora-B.
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>
Sakkiah, Sugunadevi,Meganathan, Chandrasekaran,Sohn, Young-Sik,Namadevan, Sundaraganesan,Lee, Keun Woo Molecular Diversity Preservation International (MD 2012 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.13 No.4
<P>11β-Hydroxysteroid dehydrogenase type1 (11βHSD1) regulates the conversion from inactive cortisone to active cortisol. Increased cortisol results in diabetes, hence quelling the activity of 11βHSD1 has been thought of as an effective approach for the treatment of diabetes. Quantitative hypotheses were developed and validated to identify the critical chemical features with reliable geometric constraints that contribute to the inhibition of 11βHSD1 function. The best hypothesis, Hypo1, which contains one-HBA; one-Hy-Ali, and two-RA features, was validated using Fischer’s randomization method, a test and a decoy set. The well validated, Hypo1, was used as 3D query to perform a virtual screening of three different chemical databases. Compounds selected by Hypo1 in the virtual screening were filtered by applying Lipinski’s rule of five, ADMET, and molecular docking. Finally, five hit compounds were selected as virtual novel hit molecules for 11βHSD1 based on their electronic properties calculated by Density functional theory.</P>
Sakkiah, Sugunadevi,Thangapandian, Sundarapandian,Lee, Keun Woo Springer 2012 Journal of molecular modeling Vol.18 No.7
<P>Aldose reductase 2 (ALR2), which catalyzes the reduction of glucose to sorbitol using NADP as a cofactor, has been implicated in the etiology of secondary complications of diabetes. A pharmacophore model, Hypo1, was built based on 26 compounds with known ALR2-inhibiting activity values. Hypo1 contains important chemical features required for an ALR2 inhibitor, and demonstrates good predictive ability by having a high correlation coefficient (0.95) as well as the highest cost difference (128.44) and the lowest RMS deviation (1.02) among the ten pharmacophore models examined. Hypo1 was further validated by Fisher's randomization method (95%), test set (r = 0.91), and the decoy set shows the goodness of fit (0.70). Furthermore, during virtual screening, Hypo1 was used as a 3D query to screen the NCI database, and the hit leads were sorted by applying Lipinski's rule of five and ADME properties. The best-fitting leads were subjected to docking to identify a suitable orientation at the ALR2 active site. The molecule that showed the strongest interactions with the critical amino acids was used in molecular dynamics simulations to calculate its binding affinity to the candidate molecules. Thus, Hypo1 describes the key structure-activity relationship along with the estimated activities of ALR2 inhibitors. The hit molecules were searched against PubChem to find similar molecules with new scaffolds. Finally, four molecules were found to satisfy all of the chemical features and the geometric constraints of Hypo1, as well as to show good dock scores, PLPs and PMFs. Thus, we believe that Hypo1 facilitates the selection of novel scaffolds for ALR2, allowing new classes of ALR2 inhibitors to be designed.</P>
Sakkiah, Sugunadevi,Chandrasekaran, Meganathan,Lee, Yuno,Kim, Songmi,Lee, Keun Woo Adenine Press 2012 Journal of biomolecular structure & dynamics Vol.30 No.3
<P>Sirtuin is a member of NAD(+)-dependent deacetylase family. The structural details of Sirtuin 2 (SIRT2) complex will be very useful to discover the drug which might have beneficial effects on various diseases like cancer, diabetes, etc. Unfortunately, SIRT2 complex structure is not available yet, hence molecular docking was carried out to dock the substrate (NAD(+) and acetylated lysine) and inhibitor (sirtinol) in the NAD(+) binding site. The suitable binding orientation of substrate and inhibitor in the SIRT2 active site was selected and subjected to 5 ns molecular dynamics simulations to adjust the binding orientation of inhibitor and substrate as well as to identify the conformational changes in the active site. The result provides an insight about 3D SIRT2 structural details as well as the importance of F96 in deacetylation function. In addition, our simulations revealed the displacement of F96 upon substrate and inhibitor binding, inducing an extended conformation of loop3 and changing its interactions with the rest of SIRT2. We believe that our study could be helpful to gain a structural insight of SIRT2 and to design the receptor-based inhibitors.</P>
Pharmacophore Mapping and Virtual Screening for SIRT1 Activators
Sakkiah, Sugunadevi,Krishnamoorthy, Navaneethakrishnan,Gajendrarao, Poornima,Thangapandian, Sundarapandian,Lee, Yun-O,Kim, Song-Mi,Suh, Jung-Keun,Kim, Hyong-Ha,Lee, Keun-Woo Korean Chemical Society 2009 Bulletin of the Korean Chemical Society Vol.30 No.5
Silent information regulator 2 (Sir2) or sirtuins are NAD(+)-dependent deacetylases, which hydrolyze the acetyllysine residues. In mammals, sirtuins are classified into seven different classes (SIRT1-7). SIRT1 was reported to be involved in age related disorders like obesity, metabolic syndrome, type II diabetes mellitus and Parkinson’s disease. Activation of SIRT1 is one of the promising approaches to treat these age related diseases. In this study, we have used HipHop module of CATALYST to identify a series of pharmacophore models to screen SIRT1 enhancing molecules. Three molecules from Sirtris Pharmaceuticals were selected as training set and 607 sirtuin activator molecules were used as test set. Five different hypotheses were developed and then validated using the training set and the test set. The results showed that the best pharmacophore model has four features, ring aromatic, positive ionization and two hydrogen-bond acceptors. The best hypothesis from our study, Hypo2, screened high number of active molecules from the test set. Thus, we suggest that this four feature pharmacophore model could be helpful to screen novel SIRT1 activator molecules. Hypo2-virtual screening against Maybridge database reveals seven molecules, which contains all the critical features. Moreover, two new scaffolds were identified from this study. These scaffolds may be a potent lead for the SIRT1 activation.
Pharmacophore Mapping and Virtual Screening for SIRT1 Activators
Sugunadevi Sakkiah,Navaneethakrishnan Krishnamoorthy,Poornima Gajendrarao,Sundarapandian Thangapandian,이윤호,Songmi Kim,Keun Woo Lee,서정근,Hyong-Ha Kim 대한화학회 2009 Bulletin of the Korean Chemical Society Vol.30 No.5
Silent information regulator 2 (Sir2) or sirtuins are NAD(+)-dependent deacetylases, which hydrolyze the acetyllysine residues. In mammals, sirtuins are classified into seven different classes (SIRT1-7). SIRT1 was reported to be involved in age related disorders like obesity, metabolic syndrome, type II diabetes mellitus and Parkinson’s disease. Activation of SIRT1 is one of the promising approaches to treat these age related diseases. In this study, we have used HipHop module of CATALYST to identify a series of pharmacophore models to screen SIRT1 enhancing molecules. Three molecules from Sirtris Pharmaceuticals were selected as training set and 607 sirtuin activator molecules were used as test set. Five different hypotheses were developed and then validated using the training set and the test set. The results showed that the best pharmacophore model has four features, ring aromatic, positive ionization and two hydrogen-bond acceptors. The best hypothesis from our study, Hypo2, screened high number of active molecules from the test set. Thus, we suggest that this four feature pharmacophore model could be helpful to screen novel SIRT1 activator molecules. Hypo2-virtual screening against Maybridge database reveals seven molecules, which contains all the critical features. Moreover, two new scaffolds were identified from this study. These scaffolds may be a potent lead for the SIRT1 activation.