Seung Joo Cho

Structures, energetics, and spectra of aqua‐sodium(I): Thermodynamic effects and nonadditive interactions

Using extensive ab initio calculations including electron correlation, we have studied structures, thermodynamic quantities, and spectra of hydrated sodium ions [Na(H2O)+n (n=1–6)]. Various configurations were investigated to find the stable structures of the clusters. The vibrational frequency shifts depending on the number of water molecules were investigated along with the frequency characteristics depending on the presence/absence of outer‐shell water molecules. The thermodynamic quantities of the stable structures were compared with experimental data available. Entropy‐driven structures for n=5 and particularly for n=6 are noted in the calculations, which can explain the peculiar experimental thermal energies. On the other hand, the enthalpy effect to maximize the number of hydrogen bonds of the clusters with the surrounding water molecules seems to be the dominant factor to determine the primary hydration number of Na+ in aqueous solution. The nonadditive interactions in the clusters are found to be...

Ab initio study of the complexation of benzene with ammonium cations

Abstract Complexes of benzene with ammonium cations (MenH(4−n)N+ for n=0−4) were studied using ab initio calculations with electron correlation included. The most stable structure and binding energies of the complexes are reported. The calculated binding energies are in good agreement with experiment. Two types of NH-aromatic π and CH-aromatic π interactions, which are important in biological systems, are responsible for the binding. From analysis of the structures and energies, the π-σ ∗ through-space interactions are seen to be significant in both types of NH-π and CH-π interactions.

Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain

In order to explore the interactions between flavones and P-gp, in silico methodologies such as docking and 3D-QSAR were performed. CoMFA and CoMSIA analyses were done using ligand based and receptor guided alignment schemes. Validation statistics include leave-one-out cross-validated R(2) (q(2)), internal prediction parameter by progressive scrambling (Q(*2)), external prediction with test set. They show that models derived from this study are quite robust. Ligand based CoMFA (q(2) = 0.747, Q(*2) = 0.639, r(pred)(2)=0.802) and CoMSIA model (q(2) = 0.810, Q(*2) = 0.676, r(pred)(2)=0.785) were developed using atom by atom matching. Receptor guided CoMFA (q(2) = 0.712, Q(*2) = 0.497, r(pred)(2) = 0.841) and for CoMSIA (q(2) = 0.805, Q(*2) = 0.589, r(pred)(2) = 0.937) models were developed by docking of highly active flavone into the proposed NBD (nucleotide binding domain) of P-gp. The 3D-QSAR models generated here predicted that hydrophobic and steric parameters are important for activity toward P-gp. Our studies indicate the important amino acid in NBD crucial for binding in accordance with the previous results. This site forms a hydrophobic site. Since flavonoids have potential without toxicity, we propose to inspect this hydrophobic site including Asn1043 and Asp1049 should be considered for future inhibitor design.

Structural insights from binding poses of CCR2 and CCR5 with clinically important antagonists: a combined in silico study.

Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance. Structural studies have been hampered due to the lack of X-ray crystal structures, and templates with close homologs for comparative modeling. Most of the previous models were based on the bovine rhodopsin and β2-adrenergic receptor. In this study, based on a closer homolog with higher resolution (CXCR4, PDB code: 3ODU 2.5 Å), we constructed three-dimensional models. The main aim of this study was to provide relevant information on binding sites of these receptors. Molecular dynamics simulation was done to refine the homology models and PROCHECK results indicated that the models were reasonable. Here, binding poses were checked with some established inhibitors of high pharmaceutical importance against the modeled receptors. Analysis of interaction modes gave an integrated interpretation with detailed structural information. The binding poses confirmed that the acidic residues Glu291 (CCR2) and Glu283 (CCR5) are important, and we also found some additional residues. Comparisons of binding sites of CCR2/CCR5 were done sequentially and also by docking a potent dual antagonist. Our results can be a starting point for further structure-based drug design.

Pharmacophore and docking-based combined in-silico study of KDR inhibitors

The growth and metastasis of solid tumors is dependent on angiogenesis. The vascular endothelial growth factor (VEGF) and its cell surface receptor in human KDR (kinase domain containing receptor or VEGFR-2) have particular interest because of their importance in angiogenesis. The development of novel inhibitors of VEGFR-2 would be helpful to check the growth of tumors. Quantitative structure activity relationship (QSAR) analyses used to understand the structural factors affecting inhibitory potency of thiazole-substituted pyrazolone derivatives. Several pharmacophore-based models indicated the importance of steric, hydrophobic and hydrogen bond acceptor groups to inhibitory activity. The comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analyses (CoMSIA) based 3D-QSAR models were derived using pharmacophore-based alignment. Both CoMFA (q(2)=0.70, r(2)=0.97 and r(predictive)(2)=0.61) and CoMSIA (q(2)=0.54, r(2)=0.82 and r(predictive)(2)=0.66) gave reasonable results. The molecular docking (receptor-guided technique) with a recently reported receptor structure (PDB=1YWN) were performed. The docked alignment was subsequently used for 3D-QSAR (CoMFA; q(2)=0.56, r(2)=0.97, r(predictive)(2)=0.82, CoMSIA; q(2)=0.58 r(2)=0.91, r(predictive)(2)=0.69). The overall both studies were indicated, steric, electrostatic and hydrogen bond acceptor effects contribute to the inhibitory activity. CoMFA and CoMSIA models suggested that a positive bulk with hydrophobic effect is desirable around position 4 and 5 and hydrogen bond acceptor groups around pyrazolones ring will be helpful.

Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor.

ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent and selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 microM over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 was further tested in a 10-dose IC(50) mode and showed an IC(50) value of 199 nM for ROS1 kinase. The compound 1 can be used as a promising lead for the development of new selective inhibitors for ROS1 kinase, and it may open the way for new selective therapeutics for astrocytomas.

Zn(H2O)2+6 is very stable among aqua-Zn(II) ions

Abstract Ab initio HF-SCF and MP2 calculations have been performed on Zn(H 2 O) 2+ n , where 4⩽ n ⩽8. The calculation with the Zn(8s4p2d)/O(4s2p1d)/H(2s) basis set shows that the fifth water molecule hydrating Zn(II) tends to have one more water molecule in the first hydration shell, while the seventh water molecule tends to be in the second hydration shell. Thus, we have provided evidence from ab initio calculations that hexaaqua-Zn(II) is very stable among aqua-Zn(II) ions, unless unusual thermodynamic conditions apply. The structure of the hexaaqua-Zn(II) has T h symmetry. The solvation energy contribution due to the primary hydration accounts for more than 50% of the experimental solvation energy of Zn(II). We also discuss the structure, hydration energy and spectra, comparing with experimental data.

Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors

A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209 nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed.

Aminoquinoline derivatives with antiproliferative activity against melanoma cell line

The synthesis of a novel series of aminoquinoline derivatives 1a-p and their antiproliferative activities against A375 human melanoma cell line were described. Most compounds showed superior antiproliferative activities to Sorafenib as a reference compound. Among them, quinolinyloxymethylphenyl compounds 1k and 1l exhibited potent activities (IC(50)=0.77 and 0.79microM, respectively) and excellent selectivity against melanoma and fibroblast cell lines.

Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors

Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined to explore their binding modes using FlexX, and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated q2 and non-cross validated correlation r2 coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded ‘leave one out’ q2 = 0.51 and r2 = 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation coefficients,