Biomedical subjects

Dawoon Jung

Publications and source records attributed to Dawoon Jung.

10 recordsLinked to original sources

PubMed2006

The FRB domain of mTOR: NMR solution structure and inhibitor design.

The mammalian target of rapamycin (mTOR) is a protein that is intricately involved in signaling pathways controlling cell growth. Rapamycin is a natural product that binds and inhibits mTOR function by interacting with its FKBP-rapamycin-binding (FRB) domain. Here we report on the NMR solution structure of FRB and on further studies aimed at the identification and characterization of novel ligands that target the rapamycin binding pocket. The biological activity of the ligands, and that of rapamycin in the absence of FKBP12, was investigated by assaying the kinase activity of mTOR. While we found that rapamycin binds the FRB domain and inhibits the kinase activity of mTOR even in the absence of FKBP12 (in the low micromolar range), our most potent ligands bind to FRB with similar binding affinity but inhibit the kinase activity of mTOR at much higher concentrations. However, we have also identified one low-affinity compound that is also capable of inhibiting mTOR. Hence, we have identified compounds that can directly mimic rapamycin or can dissociate the FRB binding from the inhibition of the catalytic activity of mTOR. As such, these ligands could be useful in deciphering the complex regulation of mTOR in the cell and in validating the FRB domain as a possible target for the development of novel therapeutic compounds.

Animals↗

PubMed2006

An experimental and theoretical study of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amides.

The mechanism of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amide was studied by quantum chemical calculations. The transition states of eight molecules were fully optimized at the ab initio HF/3-21G and density functional B3LYP/3-21G levels with Gaussian 98. The activation energies were calculated at the B3LYP/6-31+G(3df,2p)//B3LYP/3-21G level. We found the theoretical evaluation to be consistent with the experimental data. At the best case, an enantiomeric excess of up to 95% for (R)-2-scyclohexen-1-ol was achieved with (-)-N, N-diisopinocampheyl lithium amide.

Amides↗

PubMed2006

A structure-based approach to retinoid X receptor-alpha inhibition.

In this paper we describe a structure-based approach designed to identify novel ligands for retinoid X receptor-alpha (RXRalpha). By using a virtual approach based on a modified scoring function, we have selected 200 potential candidates on the basis of their predicted ability of docking into the ligand-binding site of the target. Subsequent experimental verification of the compounds in in vitro and cell-based assays led to the identification of a number of novel high affinity ligands for RXRalpha. The compounds are capable of displacing 9-cis-retinoic acid with IC(50) values in the 10 nm and 5 mum range and exhibit marked antagonistic activity in cellular assays. The inhibitory scaffolds discovered with this method form the basis for the development of novel RXRalpha ligands with potential therapeutic properties.

Animals↗

PubMed2006

Anthrax lethal factor protease inhibitors: synthesis, SAR, and structure-based 3D QSAR studies.

We have recently identified a series of compounds that efficiently inhibit anthrax lethal factor (LF) metallo-protease. Here we present further structure-activity relationship and CoMFA (comparative molecular field analysis) studies on newly derived inhibitors. The obtained 3D QSAR model was subsequently compared with the X-ray structure of the complex between LF and a representative compound. Our studies form the basis for the rational design of additional compounds with improved activity and selectivity.

Antigens, Bacterial↗

PubMed2005

Efficient synthetic inhibitors of anthrax lethal factor.

Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxacin against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

Animals↗

PubMed2005

Virtual docking approaches to protein kinase B inhibition.

We examined some in silico approaches to identify Akt (protein kinase B) inhibitors. Experimental validation of selected compounds was achieved using a fluorescence-based enzymatic assay and a substrate phosphorylation assay involving the protein GSK-3. We report on success and failure obtained by using several strategies including FlexX, GOLD, and CSCORE, where the 100-200 top-scoring compounds from a 50000-compound library were experimentally tested. This study led to the identification of low micromolar Akt1 inhibitors.

Adenosine Triphosphate↗

PubMed2005

Discovery of a novel class of reversible non-peptide caspase inhibitors via a structure-based approach.

In this paper, we report a simple structure-based iterative optimizations (SUBITO) strategy to identify and optimize new protein ligands and inhibitors. The approach is based on a combination of NMR-based screening and computational docking methods and enabled the identification of novel chemical leads among hundreds of thousands of commercially available compounds by screening only a few hundred compounds from a scaffold library followed by iterative screening steps where only few dozen compounds are tested. As an application, we report on the discovery of a novel class of non-peptide reversible caspase inhibitors, with IC(50) values in the low micromolar range.

Caspase 3↗

PubMed2004

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands.

The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a three-dimensional quantitative structure activity relationship (3D-QSAR) model of ligands for the sigma 1 receptor. The starting geometry of sigma-1 receptor ligands was obtained from the Tripos force field minimizations and conformations were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48 molecules were fully optimized at the ab initio HF/3-21G* and semiempirical AM1 calculations using GAUSSIAN 98. The electrostatic charges were calculated using several methods such as semiempirical AM1, density functional B3LYP/3-21G*, and ab initio HF/3-21G*, MP2/3-21G* calculations within GAUSSIAN 98. Using the optimized geometries, the CoMFA results derived from the HF/3-21G method were better than those from AM1. The best CoMFA was obtained from HF/3-21G* optimized geometry and charges (R2 = 0.977). Using the optimized geometries, the CoMFA results derived from the HF/3-21G methods were better than those from AM1 calculations. The training set of 43 molecules gave higher R2 (0.989-0.977) from HF/3-21G* optimized geometries than R2 (0.966-0.911) values from AM1 optimized geometries. The test set of five molecules also suggested that HF/3-21G* optimized geometries produced good CoMFA models to predict bioactivity of sigma 1 receptor ligands but AM1 optimized geometries failed to predict reasonable bioactivity of sigma 1 receptor ligands using different calculations for atomic charges.

Ligands↗

PubMed2004

Molecular modeling of sigma 1 receptor ligands: a model of binding conformational and electrostatic considerations.

We have performed molecular modeling studies on several sigma 1 specific ligands, including PD144418, spipethiane, haloperidol, pentazocine, and others to develop a pharmacophore for sigma 1 receptor-ligand binding, under the assumption that all the compounds interact at the same receptor binding site. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Superposition of active molecules gave the coordinates of the hypothetical 5-point sigma 1 pharmacophore, as follows: R1 (0.85, 7.26, 0.30); R2 (5.47, 2.40, -1.51); R3 (-2.57, 4.82, -7.10); N (-0.71, 3.29, -6.40); carbon centroid (3.16, 4.83, -0.60), where R1, R2 were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor; and R3 represents a hydrogen bond between the nitrogen atom and the receptor. Additional analyses were used to describe secondary binding sites to electronegative groups such as oxygen or sulfur atom. Those coordinates are (2.34, 5.08, -4.18). The model was verified by fitting other sigma 1 receptor ligands. This model may be used to search conformational databases for other possibly active ligands. In conjunction with rational drug design techniques the model may be useful in design and synthesis of novel sigma 1 ligands of high selectivity and potency. Calculations were performed using Sybyl 6.5.

Binding Sites↗

PubMed2004

NMR-based techniques in the hit identification and optimisation processes.

In this review, the use of general NMR spectroscopy techniques to detect ligand binding and to monitor enzyme kinetics and inhibition, which appear particularly useful in hit identification and validation, is reiterated. Furthermore, the use of NMR-based strategies for lead optimisations that are based on either iterative derivatisations of an initial core structure or on linking fragments that occupy adjacent pockets in the target's binding site will also be described. Several recent examples will be reported and the use of these techniques in cases when the three dimensional structure of the target protein is known will be discussed.

Binding Sites↗