A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .

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Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

Structure-antioxidant activity relationships of flavonoids and phenolic acids

This review summarizes the multifaceted aspects of antioxidants and the basic kinetic models of inhibited autoxidation and analyzes the chemical principles of antioxidant capacity assays. Depending upon the reactions involved, these assays can roughly be classified into two types:  assays based on hydrogen atom transfer (HAT) reactions and assays based on electron transfer (ET). The majority of HAT-based assays apply a competitive reaction scheme, in which antioxidant and substrate compete for thermally generated peroxyl radicals through the decomposition of azo compounds. These assays include inhibition of induced low-density lipoprotein autoxidation, oxygen radical absorbance capacity (ORAC), total radical trapping antioxidant parameter (TRAP), and crocin bleaching assays. ET-based assays measure the capacity of an antioxidant in the reduction of an oxidant, which changes color when reduced. The degree of color change is correlated with the sample's antioxidant concentrations. ET-based assays include th...

The Chemistry behind Antioxidant Capacity Assays

Atherosclerosis: The Road Ahead

Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

This paper presents a simple and convenient method for measuring antioxidant efficiencies in a model system consisting of micelles of sodium dodecyl sulfate (SDS) with added linoleic acid. The analytical method involves following the development of absorption at 230 nm due to the conjugated diene hydroperoxide of linoleic acid; 2,2'-azobis(2-amidinopropane) dihydrochloride (ABAP) is used as the initiator. The antioxidant efficiency of an antioxidant is defined as AE=k inh /k p , where k inh is the rate constant for reaction of the peroxyl radical from linoleic acid with the antioxidant (eq 7 in the text) and k p is the propagation rate constant for autoxidation of linoleic acid (eq 5)

A rapid screening test to determine the antioxidant potencies of natural and synthetic antioxidants

1. 15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the effects of PD 146176 on the development of atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks significant non specific antioxidant properties. 2. PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a Ki of 197 nM. The drug had minimal effects on either copper or 2,2'-azobis(2-amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the Ki. 3. Control New Zealand rabbits were fed a high-fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg-1, b.i.d.). Plasma concentrations of inhibitor were similar to the estimated Ki (197 nM). During the 12 week study, there were no significant differences in weight gain haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol. 4. The drug plasma concentrations achieved in vivo did not inhibit low-density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176-treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP. 5. PD 146176 was very effective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15 +/- 4 to 0% (P < 0.02); esterified cholesterol content was reduced from 2.1 +/- 0.7 to 0 micrograms mg-1 (P < 0.02) in this region. Immunostainable lipid-laden macrophages present in aortic intima of control animals were totally absent in the drug-treated group. 6. Results of these studies are consistent with a role for 15-LO in atherogenesis.

Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties

This invention provides a method for treating or preventing inflammation or atherosclerosis in mammals comprising administering an effective amount of a 15-LO inhibitor of Formula I: ##STR1## wherein: R1 is hydrogen or C1 -C6 alkyl; R2, R3, R4, and R5 independently are hydrogen, C1 -C6 alkyl, nitro, halo, CN, OR6, NR6 R7, --CO2 R6, CONR6 R7, CH2 OR6, or CH2 NR6 R7, and R2 and R3, and R4 and R5, when attached to adjacent ring atoms, can be --(CH2)3 or 4 --; in which R6 and R7 independently are hydrogen, C1 -C6 alkyl, phenyl or benzyl, and when taken together with the nitrogen to which they are attached, R6 and R7 can complete a cyclic ring having from 3 to 7 carbon atoms; ##STR2## in which R8, R8', R9, and R9' independently are hydrogen or C1 -C6 alkyl, n is 0, 1, or 2, and Z.sup.⊖ is an anion, and pharmaceutically acceptable salts thereof.

Method for treating and preventing inflammation and atherosclerosis

Novel Series of Achiral, Low Molecular Weight, and Potent HIV-1 Protease Inhibitors

HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains an important goal. Using an HIV-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affinity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl]-2H-1-benzopyran-2-one (31).

Bradley Dean Tait

Papers

A rapid screening test to determine the antioxidant potencies of natural and synthetic antioxidants

Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties

Method for treating and preventing inflammation and atherosclerosis

Novel Series of Achiral, Low Molecular Weight, and Potent HIV-1 Protease Inhibitors

A Novel Nonpeptide HIV-1 Protease Inhibitor: Elucidation of the Binding Mode and Its Application in the Design of Related Analogs