Biomedical subjects

J S Tokarski

Publications and source records attributed to J S Tokarski.

5 recordsLinked to original sources

PubMed2000

Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.

Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperidone 10 was obtained from the racemic piperidone 8 via a very efficient "dynamic kinetic resolution" in 76% yield. Hydrophobic side chains such as chlorophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hydrophilic side chains such as pyrimidine or aniline caused a severe reduction in CDK inhibitory activity. These analogues are competitive inhibitors with respect to ATP, and therefore activity was dependent upon the CDK subunit without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine protein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol.

Antineoplastic Agents↗

PubMed1997

Molecular modeling of polymers 16. Gaseous diffusion in polymers: a quantitative structure-property relationship (QSPR) analysis.

PURPOSE: The purpose of this study was to identify the key physicochemical molecular properties of polymeric materials responsible for gaseous diffusion in the polymers. METHODS: Quantitative structure-property relationships, QSPRs were constructed using a genetic algorithm on a training set of 16 polymers for which CO2, N2, O2 diffusion constants were measured. Nine physicochemical properties of each of the polymers were used in the trial basis set for QSPR model construction. The linear cross-correlation matrices were constructed and investigated for colinearity among the members of the training sets. Common water diffusion measures for a limited training set of six polymers was used to construct a "semi-QSPR" model. RESULTS: The bulk modulus of the polymer was overwhelmingly found to be the dominant physicochemical polymer property that governs CO2, N2 and O2 diffusion. Some secondary physicochemical properties controlling diffusion, including conformational entropy, were also identified as correlation descriptors. Very significant QSPR diffusion models were constructed for all three gases. Cohesive energy was identified as the main correlation physicochemical property with aqueous diffusion measures. CONCLUSIONS: The dominant role of polymer bulk modulus on gaseous diffusion makes it difficult to develop criteria for selective transport of gases through polymers. Moreover, high bulk moduli are predicted to be necessary for effective gas barrier materials. This property requirement may limit the processing and packaging features of the material. Aqueous diffusion in polymers may occur by a different mechanism than gaseous diffusion since bulk modulus does not correlate with aqueous diffusion, but rather cohesive energy of the polymer.

Carbon Dioxide↗

PubMed1994

Three-dimensional molecular shape analysis-quantitative structure-activity relationship of a series of cholecystokinin-A receptor antagonists.

The three-dimensional molecular shape analysis-quantitative structure-activity relationship (3D-MSA-QSAR) technique has been applied to develop correlations between the calculated physicochemical properties and the in vitro activities of a series of 3-(acylamino)-5-phenyl-2H-1,4-benzodiazepine cholecystokinin-A (CCK-A) antagonists. 3D-MSA-QSARs were developed for varying subsets of 53 analogs (J. Med. Chem. 1988, 31, 2235-2246). An active conformation is hypothesized for these compounds using the loss in biological activity-loss in conformational stability principle. After placing all compounds in the active conformation and performing pairwise molecular shape analysis, it was determined that not any one analog serves as the best shape reference compound. Nonidentical volumes of allowed receptor space are mapped out by different antagonists. A shape reference compound that consists of selected overlapped structures expands the definition of the accessible receptor space. This type of mutant improves the predicted activity of analogs over the value predicted if only one compound is chosen as the reference. Molecular shape, as represented by common overlap steric volume and nonoverlap steric volume, is the major factor contributing to the affinity of this class of compounds. Intramolecular conformational stability, as measured by the difference in energy of the active conformation and the global minimum energy conformation, is also important. It is further concluded from the 3D-MSA-QSAR models that part of the binding pocket for the 3-amido substituent has a preference for lipophilicity. The method used in this study of fragmenting the antagonist into spheres of varying radii and measuring lipophilicity isolates the substructure with highest probability of interacting with the receptor. Two indicator variables marking the presence of an N-methyl group and an o-fluoro atom on the 5'-phenyl substituent of the benzodiazepine ring structure also contribute significantly to the 3D-MSA-QSAR models. The 3D-MSA-QSAR results have led to the proposal of a 3D pharmacophore model for the benzodiazepine CCK-A antagonists.

Animals↗

PubMedDate not supplied

Constructing protein models for ligand-receptor binding thermodynamic simulations: an application to a set of peptidometic renin inhibitors.

Structure-based design is the application of ligand-receptor modeling to predict the activity of a series of molecules that bind to a common receptor for which the molecular geometry is available. Successful structure-based design requires an accurate receptor model which can be economically employed in the design calculations. One goal of the work reported here has been to reduce the size of a model structure of a macromolecular receptor to allow multiple ligand-receptor molecular dynamic (MD) simulations to be computationally economical yet still provide meaningful binding thermodynamic data. A scaled-down 10 A receptor model of the enzyme renin, when subjected to an alternate atomic mass constraint, maintains the structural integrity of the composite parent crystal structure. A second goal of the work has been to develop schemes to explore and characterize the protonation states of receptors and ligand-receptor systems. Application of the charge state characterization schemes to the hydroxyethylene and statine transition state inhibitors of renin in the training set suggests a monoprotonation state of the two active-site aspartate residues, where the lone proton resides on the outer carboxylate oxygen of Asp226 is most likely. For the reduced amide transition state inhibitors an active site consisting of both aspartates in the totally ionized state, and the ligand carrying a net +1.0 charge, is most stable and consistent with experimental data.

Amino Acid Sequence↗

PubMedDate not supplied

Prediction of ligand-receptor binding thermodynamics by free energy force field (FEFF) 3D-QSAR analysis: application to a set of peptidometic renin inhibitors.

A methodology is presented and applied in which the accurate estimation of ligand-receptor binding thermodynamics is achieved by formulating the calculation as a QSAR problem. When the receptor geometry is known, the free energy force field (FEFF) ligand-receptor binding energy terms can be calculated and used as independent variables in constructing FEFF 3D-QSARs. The FEFF 3D-QSAR analysis of a series of transition state inhibitors of renin was carried out. From a statistical analysis of the free energy contributions to the binding process, FEFF 3D-QSARs were constructed that reveal the change in solvation free energy upon binding and the intramolecular vacuum internal energy of the ligand in the unbound state are the most significant FEFF terms in determining the binding free energy, delta G. Other terms, such as ligand stretching, bending, and torsion energy changes, the intermolecular van der Waals interaction energy, and change in ligand conformational entropy upon binding, are also found to make significant contributions in some FEFF 3D-QSAR delta G models and in delta H and delta S binding models. Overall, a relatively small number of the thermodynamic contributions to the ligand-receptor binding process dominates the thermodynamics of binding in a given model.

Amino Acid Sequence↗