Shijun Ren

Quantitative structure-activity relationship analysis of phenolic antioxidants

In this report, the quantitative structure-activity relationship (QSAR) analyses of substituted phenols, vitamin E derivatives and flavonoids are presented. Two models have been derived using calculated parameters such as the heat of formation (Hf), the energy of the lowest unoccupied molecular orbital of radicals (E(lumo-r)) the energy of the highest occupied molecular orbital of the parent compounds (E(homo)) and the number of hydroxyl groups (OH). These models can be used to estimate the redox potentials or antioxidant activities of new substituted phenolic compounds or vitamin E derivatives. The Trolox equivalent antioxidant capacities (TEACs) of 42 different flavonoids are found to be mainly governed by the number and location of hydroxyl groups on the flavonoid ring system.

Inhibition of herpes simplex virus type 1 and adenovirus type 5 by heterocyclic Schiff bases of aminohydroxyguanidine tosylate

Abstract Eleven heterocyclic Schiff bases of aminohydroxyguanidine tosylate (SB-AHGs), compounds I–XI, were tested for antiviral activity against herpes simplex virus type 1 (HSV-1) and adenovirus type 5 (Ad 5) via plaque reduction and virus yield reduction assays. This work was undertaken to test the hypothesis that low molecular weight SB-AHGs (MW<235 for the free SB) make better antiviral agents than high MW SB-AHGs (MW>300). The plaque reduction assay method demonstrated that three compounds, I, VII and IX, had moderate activity against HSV-1, with 50% inhibitory concentration (IC50) values of 38.0, 23.5 and 52.1 μM, respectively. Against Ad 5, compounds I, VIII and XI exhibited moderate activity, with IC50 values of 52.7, 19.3 and 5.1 μM, respectively. Among the compounds screened, compound I (1-[(3′-hydroxy-6′-methyl-2′-pyridyl)methylene]amino-3-hydroxyguanidine tosylate) was the most promising antiviral candidate, with selectivity indices (SI) of 10.2 (HSV-1) and 7.6 (Ad 5), respectively. Virus yield reduction assays indicated that compound I had less antiviral potency against HSV-1 than against Ad 5. The antiviral effects of compound I at a high input virus multiplicity of infection (MOI>5) indicated that compound I had effective anti-adenoviral activity at 24 h post infection. This work demonstrated that some of SB-AHGs only have moderate antiviral activities against Ad 5 and HSV-1 viruses. In general, low MW SB-AHGs have low cytotoxicities to the host cells.

Caco-2 cell permeability vs human gastro-intestinal absorption: QSPR analysis

The aim of this study is to elucidate quantitative structure-permeability relationship (QSPR) of various organic molecules through Caco-2 cells, and to ascertain the relationship between gastrointestinal (GI) absorption in humans and Caco-2 cell permeability. Caco-2 cell permeability and human GI absorption data were obtained from the literature. The maximum hydrogen bond-forming capacity corrected for intra-molecular H-bonding (Hbc) and Liens QSAR model were used in this study. The latest CQSAR software was utilized in calculating the logarithm of partition coefficient in octanol/water (Clog P) and in deriving all regression equations. For 51 compounds, a significant correlation was obtained between Caco-2 cell permeability (log Pcaco-2) and Hbc, octanol/PBS (phosphate buffered saline, pH 7.4) distribution coefficient (log Doct), log MW and an indicator variable (I) for the charge, with a correlation coefficient of 0.797. When these compounds were divided into three subgroups, namely neutral, cationic and anionic compounds, much better correlations (r = 0.968, 0.915 and 0.931, respectively) were obtained using different combinations of various physico-chemical parameters. A plot of human GI absorption vs. Caco-2 cell permeability obtained from different laboratories reveals that Caco-2 cell permeability cannot be used to precisely predict human GI absorption for compounds with Pcaco-2 below 5 x 10(-6) cm/s, due to interlaboratory and experimental variabilities, and the lack of a simple correlation between human GI absorption and Caco-2 cell permeability. Caco-2 cell permeability may be estimated from the structures of drug molecules using the above-mentioned physicochemical parameters. In general, for compounds with Pcaco-2 above 5 x 10(-6) cm/s, human GI absorption ranges from 50 to 100%. This is generally acceptable for development into oral dosage form. For the compounds with Pcaco-2 below 5 x 10(-6) cm/s, careful interpretation of caco-2 cell permeability and use of internal standard for comparison are recommended. Otherwise, good drug candidates may be excluded due to incorrectly predicted poor absorption.

QSAR analysis of membrane permeability to organic compounds

A general mathematical model involving partition coefficient, molecular weight and hydrogen bonding is used to correlate the structures and permeability of various organic compounds through the toad urinary bladder and human red blood cell (RBC) membranes. Log Per (permeability) is correlated with log Po/w (partition coefficient in olive oil/water, or ether/water), log MW (molecular weight) and Hb (hydrogen bonds). Log Po/w is the most important factor among three parameters examined. While increased MW always has a negative effect on the permeability, increased Hb can have either a slightly positive or a slightly negative effect depending on the solvent and membrane systems used. Systematic comparison of the QSARs (quantitative structure activity relationship) of different biological membranes may serve as a useful guide in drug targeting to different tissues and cell types.

Natural products and their derivatives as cancer chemopreventive agents

This review summarizes currently available data on the chemopreventive efficacies, proposed mechanisms of action and relationships between activities and structures of natural products like vitamin D, calcium, dehydroepidandrosterone, coenzyme Q10, celery seed oil, parsley leaf oil, sulforaphane, isoflavonoids, lignans, protease inhibitors, tea polyphenols, curcumin, and polysaccharides from Acanthopanax genus.

Development of HIV protease inhibitors : A survey

In the treatment of infections caused by rapidly mutating viruses like human immunodeficiency virus (HIV), combination therapy with multiple drugs acting by different mechanisms offers several advantages over monotherapy. It may provide: synergistic effect, possible reduction of dosages and side-effects, and reduction of the chance of drug resistance. In the past few years, hundreds of HIV protease inhibitors have been synthesized and tested in order to overcome the limitations of reverse transcriptase inhibitors like zidovudine and others. In this review, emphasis is placed on the development of HIV protease inhibitors as antiviral agents against HIV, and structure-activity relationship analysis of saquinavir and related compounds. Limitations of some protease inhibitors and ways to overcome the shortcomings are presented. Among these many protease inhibitors five have been marketed during 1995-1999. They are saquinavir, ritonavir, indinavir, nelfinavir and amprenavir. Their different structural features, important physicochemical, pharmacokinetic and clinical profiles are presented in a table form for easy comparison. It is hoped that in the future new drugs based on additional mechanisms can be developed for the treatment of AIDS.

Dihydroorotate Dehydrogenase Inhibitors: Quantitative Structure-activity Relationship Analysis

AbstractPurpose. The main purpose of this study is to analyze the quantitative structure-activity relationship of two series of dihydroorotate dehydrogenase inhibitors (leflunomide and quinoline carboxylic acid analogues), and to determine the structural requirements for optimum activity of these analogues. Methods. A new CQSAR program was used in deriving regression equations and calculating the octanol/water partition coefficient and the molar refractivity values. The molecular modeling was performed using the HyperChem® program. Results. Statistically significant correlations were obtained using a combination of 3−4 parameters. The structural requirements for optimum activity and critical regions for the inhibitory activity of dihydroorotate dehydrogenase were identified. Conclusions. The quantitative structure-activity relationship analysis demonstrated that two series of dihydroorotate dehydrogenase inhibitors may bind to different binding sites on the enzyme. These results provide a better understanding of dihydroorotate dehydrogenase inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme.

Purine analogs as CDK enzyme inhibitory agents: a survey and QSAR analysis.

Characterization of the cell cycle has introduced CDKs and other proteins as possible targets for inhibition of cell proliferation, such as, CDK1 and CDK2, whose inhibition may be useful in the treatment of proliferative disorders. Structure-activity analyses have been instrumental in the design and discovery of potent CDK inhibitors, such as purine analogs, which have increased in potency from the micromolar to the nanomolar level. X-ray crystallography and molecular modeling have provided evidence that these compounds act on the CDK target enzyme. Selected CDK inhibitors have successfully entered clinical trials. Further characterization of the cell cycle to identify molecular targets to inhibit cell proliferation, QSAR and SAR studies, and clinical trials may expedite the development of CDK inhibitors for therapeutic use. The ultimate goal of these studies is to determine whether specific CDKs, CDK1 or CDK2, are enzymes essential to cell proliferation that can be targeted for treatment of proliferative disorders. CDK1 and CDK2 are viable molecular targets for cancer therapies based on isolated-enzyme inhibition by CDK inhibitors, successful clinical trials of CDK1 and CDK2 inhibitors, and x-ray crystallographic confirmation of CDK inhibitors binding to the putative target enzyme active site. It is now reported that CDK1 inhibitory activities of purine analogs correlate with the physiochemical parameters of purine analogs. Enzyme inhibition [1-5], clinical trials (see Tab. 1), x-ray crystallographic [4, 6, 7] and QSAR correlation studies are evidence that specific CDK1 and/or CDK2 inhibitors are potentially useful agents for various cell-proliferation disorders. A brief overview of the cell cycle precedes a literature review of clinical applications of CDK inhibitors, followed by a new QSAR study, and a SAR and molecular modeling discussion.

Physicochemical basis of the universal genetic codes — quantitative analysis

Quantitative mathematic models have been developed to correlate the fragment hydrophobicity contribution constants (faa) of 20 amino acids with the physicochemical properties (mu, Hb, and square root of MW) of the four bases (U, A, C, G) of the codons, or those of the anticodons. Using the general equation faa = a mu 1 + b mu 2 + c mu 3 + d square root of MW1 + e square root of MW2 + f square root of MW3 + g Hb1 + h Hb2 + i Hb3 + j, where 1, 2, 3 refer to the first, the second and the third base respectively, correlation coefficient of about 0.82 can be obtained for all 20 amino acids coded by 61 different triplet codes. These correlations are statistically highly significant, even though they do not take into account the involvement of various factors and peptidyl transferases. Furthermore, the reasons for the three stop codons are revealed. The graphic presentation of the codons and the amino acids coded separates the acidic and the basic, the aromatic and the heterocyclic amino acids into different quadrants of an octagon. This is in agreement with the ancient Chinese Ying-Yang theory embedded in the classical I-Ching.