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Sun Choi

Publications and source records attributed to Sun Choi.

6 recordsLinked to original sources
PubMed2006

Balancing focused combinatorial libraries based on multiple GPCR ligands.

G-Protein coupled receptors (GPCRs) are important targets for drug discovery, and combinatorial chemistry is an important tool for pharmaceutical development. The absence of detailed structural information, however, limits the kinds of combinatorial design techniques that can be applied to GPCR targets. This is particularly problematic given the current emphasis on focused combinatorial libraries. By linking an incremental construction method (OptDesign) to the very fast shape-matching capability of ChemSpace, we have created an efficient method for designing targeted sublibraries that are topomerically similar to known actives. Multi-objective scoring allows consideration of multiple queries (actives) simultaneously. This can lead to a distribution of products skewed towards one particular query structure, however, particularly when the ligands of interest are quite dissimilar to one another. A novel pivoting technique is described which makes it possible to generate promising designs even under those circumstances. The approach is illustrated by application to some serotonergic agonists and chemokine antagonists.

Combinatorial Chemistry Techniques↗
PubMed2002

Inactivation and inhibition of gamma-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues.

Four cyclohexene analogues of gamma-aminobutyric acid (GABA) and beta-alanine were designed as conformationally rigid analogues of the epilepsy and drug addiction drug vigabatrin and as potential mechanism-based inactivators of gamma-aminobutyric acid aminotransferase (GABA-AT). The corresponding cyclopentene analogues were previously reported to be inhibitors, but not inactivators, of GABA-AT (Qiu, J.; Pingsterhaus, J.; Silverman, R. B. J. Med. Chem. 1999, 42, 4725-4728). cis-3-Aminocyclohex-4-ene-1-carboxylic acid (3) and cis-2-aminocyclohex-3-ene-1-carboxylic acid (5) showed time- and concentration-dependent, irreversible inactivation of GABA-AT. In both cases, the inactivations are protected by substrate, indicating that they are active site-directed. trans-3-Aminocyclohex-4-ene-1-carboxylic acid (4) and trans-2-aminocyclohex-3-ene-1-carboxylic acid (6) are not inactivators but are competitive reversible inhibitors of GABA-AT. Unlike the cyclopentene analogues, there appears to be sufficient ring flexibility to allow inactivation to occur. The orientation of the carboxylic and amino groups of these analogues is important for their binding to GABA-AT. Molecular modeling of GABA-AT with 3-6 and molecular dynamics simulations with vigabatrin bound provide rationalizations for the inhibitory properties of these compounds.

4-Aminobutyrate Transaminase↗
PubMed2002

Design of a conformationally restricted analogue of the antiepilepsy drug Vigabatrin that directs its mechanism of inactivation of gamma-aminobutyric acid aminotransferase.

The antiepilepsy drug vigabatrin (1, 4-aminohex-5-enoic acid, gamma-vinylGABA) is known to be a mechanism-based inactivator of the pyridoxal phosphate (PLP)-dependent enzyme gamma-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M.; Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9341-9349). The major pathway involves gamma-proton removal, tautomerization into the PLP ring, followed by Michael addition of an active site lysine residue at the conjugated vinyl group to give a stable covalent adduct with the protein (Scheme 2, pathway a). The minor inactivation mechanism also involves gamma-proton removal, but tautomerization occurs through the vinyl group, followed by an enamine rearrangement that leads to attachment of the inactivator to the PLP, which is bound to the protein (Scheme 2, pathway b). The cause for the two different inactivation pathways was hypothesized to be potential overlap of the incipient carbanion with the pi-orbitals of both the PLP and the vinyl group. With use of the crystal structure data for GABA-AT recently reported (Storici, P.; Capitani, C.; De Biase, D.; Moser, M.; John, R. A.; Jansonius, J. N.; Schirmer, T. Biochemistry 1999, 38, 8628-8634) a computer model of vigabatrin bound to the PLP was constructed and energy minimized. This model indicated that the major Michael addition pathway could only occur if the vinyl group were allowed to rotate by 180 degrees. A conformationally rigid analogue of vigabatrin, cis-3-aminocyclohex-4-ene-1-carboxylic acid (9), was designed to prevent bond rotation and block the Michael addition pathway. A detailed study of the mechanism of inactivation of GABA-AT by 9 revealed that it inactivates by a single mechanism, the enamine pathway.

4-Aminobutyrate Transaminase↗
PubMedDate not supplied

The effects of biasing torsional mutations in a conformational GA.

This paper describes the effects of incorporating torsional bias into a conformational Genetic Algorithm (GA) such as that found in the GASP program. Several major conclusions can be drawn. Biasing torsional angles toward values associated with local energy minima increases the rate of convergence of the fitness function (consisting of energy, steric, and pharmacophoric compatibility terms) for a set of molecules, but a definite tradeoff exists between total model energy and the steric and pharmacophoric compatibility terms in the fitness score. Biasing torsions in favor of sets of angles drawn from low-energy conformations does not guarantee low total energy, but biased torsional sampling does generally produce less strained models than does the uniform torsional sampling in classical GASP. Overall, torsionally biased sampling produces good models comprised of energetically favorable ligand conformations.

Algorithms↗