The impact of physicochemical and molecular properties in drug design: navigation in the "drug-like" chemical space.

Physicochemical and molecular properties influence both pharmacokinetic and pharmacodynamic process, as well as drug safety, often in a conflicting way. In this aspect the current trend in drug discovery is to consider ADME (T) properties in parallel with target affinity. The concept of "drug-likeness" defines acceptable boundaries of fundamental properties formulated as simple rules of thumb, in order to aid the medicinal chemist to prioritize drug candidates.

Investigation of the retention behavior of structurally diverse drugs on alpha(1) acid glycoprotein column: insight on the molecular factors involved and correlation with protein binding data.

Retention of 49 structurally diverse drugs on alpha1 acid glycoprotein column was investigated under different chromatographic conditions. Acetonitrile and 2-propanol were used as organic modifiers at different percentages and the pH was adjusted at 7.0 using PBS.

Octanol/water partitioning simulation by RP-HPLC for structurally diverse acidic drugs: comparison of three columns in the presence and absence of n-octanol as the mobile phase additive.

The advantageous effect of n-octanol as a mobile phase additive for lipophilicity assessment of structurally diverse acidic drugs both in the neutral and ionized form was explored. Two RP C18 columns, ABZ+ and Aquasil, were used for the determination of logkw indices, and the results were compared with those previously reported on a base-deactivated silica column. At pH 2.

Analysis of PPAR-α/γ Activity by Combining 2-D QSAR and Molecular Simulation.

In the present study 2D-QSAR analysis was combined with information on crystallographic data and molecular modeling, in order to investigate dual PPAR-α/γ activity for a data set of 71 compounds, compiled from literature. Using Multivariate Data Analysis, satisfactory PLS models were generated for each receptor subtype separately. The models were based on simple and easily interpretable drug-like and constitutional descriptors, while the inclusion of MOLCONN-Z descriptors in the initial pool of variables had no considerable impact in model predictivity.

The performance of 1-ethyl-3-methylimidazolium tetrafluoroborate ionic liquid as mobile phase additive in HPLC-based lipophilicity assessment.

Ionic liquids have been widely used as green alternative mobile phase additives to shield the residuals silanols groups and modify the stationary/mobile phase HPLC systems. The present study aimed to evaluate the performance of the ionic liquid 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4]) in producing extrapolated logk(w) indices suitable to substitute for octanol-water logP or logD values. The effect of [EMIM][BF4] was investigated for a set of basic and neutral drugs using two different columns, BDS and ABZ(+) .

Retention of structurally diverse drugs in human serum albumin chromatography and its potential to simulate plasma protein binding.

The retention behavior of 39 structurally diverse neutral, basic and acidic drugs was investigated on an HSA stationary phase using PBS buffer (pH 7.0) and acetonitrile or 2-propanol as organic modifiers. Extrapolated or directly measured logk(w) values as well as isocratic retention factors were correlated with plasma protein binding data taken from the literature.

Evaluation of FAK and Src expression in human benign and malignant thyroid lesions.

Focal Adhesion Kinase (FAK) and Src have been reported to regulate tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate by immunohistochemistry the clinical significance of FAK and Src expression in 108 patients with benign and malignant thyroid lesions. Total FAK expression provided a distinct discrimination between malignant and benign (p = 0.

Direct injection liquid chromatography/positive ion electrospray ionization mass spectrometric quantification of methotrexate, folinic acid, folic acid and ondansetron in human serum.

A rapid liquid chromatography/positive ion electrospray mass spectrometric assay (LC/ESI-MS) was developed for the quantitation of methotrexate, folinic acid, folic acid and ondansetron in human serum. The assay was based on 100microL serum samples, following acetonitrile precipitation of proteins and filtration that enabled direct injection into the LC/MS system. All analytes and the internal standard, alfuzosin, were separated by using a Zorbax Eclipse XDB-C(8) analytical column (2.

Application of quantitative structure-activity relationships for modeling drug and chemical transport across the human placenta barrier: a multivariate data analysis approach.

Pharmacological agents and environmental pollutants can transfer from mother to fetus across the placental barrier, leading to reproductive toxic effects. Ex vivo human placental perfusion constitutes the most widely used method to study placental transfer and metabolism of drugs and chemicals. The aim of the present study was to evaluate whether quantitative structure-activity relationship (QSAR) methodology could serve as an effective alternative tool to estimate drugs and chemicals transport across the human placental barrier on the basis of easily interpretable molecular, physicochemical and structural properties.

Structural basis for the design of PPAR-gamma ligands: a survey on quantitative structure- activity relationships.

The present review after providing a short overview on PPARs and their pleiotropic action focuses on the QSAR studies reported mainly for PPAR-gamma agonists. The different 3D and 2D QSAR models are discussed, their impact in better understanding of the mechanism of action is analyzed and their contribution in the design of new molecules is outlined.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands as potential therapeutic agents to treat arthritis.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has already been considered as an attractive molecular target for the treatment of human metabolic disorders. Pleiotropic functions beyond this limit, such as anti-inflammatory and anti-proliferative effects against several pathological states, including atherosclerosis, osteoporosis and cancer, are currently being explored. Several natural and synthetic PPAR-gamma ligands have been the focus of extensive research effort as potent anti-inflammatory agents in diverse disease states.

Diagnostic and prognostic utility of serum receptor-binding cancer antigen expressed on SiSo cells (RCAS1) levels in colon cancer patients.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that induces cell-cycle arrest and/or apoptosis in cells bearing the RCAS1 receptor. The aim of the present study was to elucidate the diagnostic and prognostic utility of RCAS1 levels in colon cancer patients. Serum RCAS1 levels were determined using a sandwich enzyme-linked immunosorbent assay in 97 colon cancer patients and 20 healthy individuals.

Quantitative structure-activity relationship (QSAR) methodology in forensic toxicology: modeling postmortem redistribution of structurally diverse drugs using multivariate statistics.

Postmortem redistribution (PMR) constitutes a multifaceted process, which renders the analytical results of drug concentrations inaccurate to be interpreted by forensic toxicologists. The aim of the present study was to evaluate whether quantitative structure-activity relationship (QSAR) methodology could serve as an effective tool to estimate the ability of drugs to redistribute across tissue barriers during postmortem period on the basis of their molecular, physicochemical and structural properties. In this aspect, multivariate data analysis (MVDA) was applied to a set of 77 structurally diverse drugs.

Involvement of hepatic stimulator substance in experimentally induced fibrosis and cirrhosis in the rat.

Liver fibrosis results from sustained wound healing response to chronic liver injury. Liver cirrhosis, the end stage of the fibrotic process, is characterized by disruption of the entire liver architecture and reduced hepatocyte regenerative ability. Hepatic stimulator substance (HSS) is a liver-specific growth factor triggering hepatocyte proliferation in vitro and in vivo.

Quantitative structure-activity relationships for PPAR-gamma binding and gene transactivation of tyrosine-based agonists using multivariate statistics.

Peroxisome proliferator-activated receptor-gamma offers a molecular target for drugs aimed to treat type II diabetes mellitus, while its therapeutic potency against cancer disease is currently being explored in preclinical studies. Tyrosine derivatives constitute a major class of peroxisome proliferator-activated receptor-gamma agonists attracting considerable research interest in drug discovery. Thus, the establishment of adequate QSAR models would serve as a guide for further molecular design.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: novel pharmacological agents in the treatment of ischemia reperfusion injury.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands constitute important insulin sensitizers that have already been used for the treatment of human metabolic disorders, exerting also pleiotropic effects on inflammatory related diseases and cancer. Ischemia-reperfusion injury that is mainly associated with organ transplantation constitutes a serious complication with a great relevance in clinical practice. Accumulating experimental data have recently revealed that natural and synthetic PPAR-gamma ligands exert beneficial effects against ischemia-reperfusion injury.

Chromatographic behavior of zwitterionic enalapril-exploring the conditions for lipophilicity assessment.

The chromatographic behavior of enalapril was investigated under different stationary and mobile phase conditions in an effort to unravel interferences in the underlying retention mechanism, which would affect its relation to octanol-water partitioning. Extrapolated retention factors, logk(w), were used as relevant chromatographic indices. The retention/pH profile was established and the peak split phenomenon, associated with cis/trans interconversion, was also monitored as a function of pH.

PPAR-gamma signaling pathway in placental development and function: a potential therapeutic target in the treatment of gestational diseases.

Background: PPAR-gamma is a target for the treatment of metabolic disorders, as Pioglitazone and Rosiglitazone are already used against type 2 diabetes. Pleiotropic functions, such as antiproliferative and anti-inflammatory effects against several pathological states, including cardiovascular disease and cancer, are currently being explored in clinical studies.

Objective: Evidence indicates that PPAR-gamma is expressed in the placenta, playing a crucial role in placental development and function, while PPAR-gamma ligands appear to modulate fetal membrane signals.

Coxsackievirus and adenovirus receptor expression in human endometrial adenocarcinoma: possible clinical implications.

The coxsackievirus and adenovirus receptor (CAR) is a crucial receptor for the entry of both coxsackie B viruses and adenoviruses into host cells. CAR expression on tumor cells was reported to be associated with their sensitivity to adenoviral infection, while it was considered as a surrogate marker for monitoring and/or predicting the outcome of adenovirus-mediated gene therapy. The aim of the present study was to evaluate the clinical significance of CAR expression in endometrial adenocarcinoma.

Alternative measures of lipophilicity: from octanol-water partitioning to IAM retention.

This review describes lipophilicity parameters currently used in drug design and QSAR studies. After a short historical overview, the complex nature of lipophilicity as the outcome of polar/nonpolar inter- and intramolecular interactions is analysed and considered as the background for the discussion of the different lipophilicity descriptors. The first part focuses on octanol-water partitioning of neutral and ionisable compounds, evaluates the efficiency of predictions and provides a short description of the experimental methods for the determination of distribution coefficients.

Peroxisome Proliferator-Activated Receptor-gamma Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-gamma ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis.

Electrostatic interactions and ionization effect in immobilized artificial membrane retention. A comparative study with octanol-water partitioning.

The present study is a continuation of our efforts to investigate the effect of electrostatic interactions and ionization on immobilized artificial membrane (IAM) retention. The previous set of neutral and basic drugs was extended to include acids and ampholytes and analogous buffer conditions in the mobile phase were used, namely morpholinepropanesulfonic acid and phosphate buffer saline, adjusted at pH 7.4.

DNA repair alterations in common pediatric malignancies.

DNA repair is an important defense mechanism against DNA damage and includes four distinct pathways: direct, excision, mismatch, and double-strand break repair systems. Recent evidence suggests that alterations in proteins participating in the DNA repair systems may result in cellular senescence, cell death, and neoplastic transformation. Malignancies in adulthood exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair.

Peroxisome proliferator-activated receptor-gamma ligands as investigational modulators of angiogenesis.

PPAR-gamma ligands constitute important insulin sensitizers that have already been approved for the treatment of human metabolic disorders. They also exert pleiotropic effects on cell proliferation and cancer and are now being explored in preclinical studies. Angiogenesis constitutes a multifaceted process that is implicated in tumor development and other benign disease states that are associated with diabetes.

Contribution to the standardization of the chromatographic conditions for the lipophilicity assessment of neutral and basic drugs.

The chromatographic conditions aiming to a better simulation of n-octanol-water partitioning using a base deactivated silica (BDS) column as stationary phase were investigated for structurally diverse basic and neutral drugs. Extrapolated retention factors log k(w), determined using different methanol fractions as organic modifier, were considered as lipophilicity indices. The effect of n-decylamine and n-octanol as mobile phase additives was examined and the appropriateness of the final retention outcome to reproduce lipophilicity data was evaluated.