Mini Reviews in Medicinal Chemistry - Volume 8, Issue 1, 2008

Liver diseases afflict more than 10% of the world population. Although the main risk factors are known and the population at risk is monitored, new biomarkers are urgently needed to allow early diagnosis and hence more effective therapeutic interventions. Here, we revise the contribution of proteomics to the study of liver diseases and its potential impact in the clinical practice is evaluated.

Since 1990 eight new antiepileptic drugs (AEDs) have been developed. Among these new drugs, Topiramate (TPM) is one of the latest AEDs available for treating drug resistant partial epilepsy both in adults and in children. The mechanisms underlying TPM antiepileptic activity are still incompletely understood. However, TPM, a sulfamatesubstituted derivative of the naturally occurring monosaccharide D-fructose, has a different structure from other known AEDs. The antiepileptic activity of TPM in animal models of partial and generalized tonic-clonic seizures has been shown to be more effective as compared to other AEDs. Proposed mechanisms of action include reduction of epileptiform discharges through a voltage-dependent block of Na+ channels, enhancement of the activity of γ-aminobutyrate at some subtypes of γ-aminobutyrate receptors, and antagonism of non- N-methyl-D-aspartate (NMDA) glutamate receptors. The pharmacokinetic profile of TPM, which is characterized by its rapid and almost complete absorption after oral administration, linear pharmacokinetics, minimal protein binding and predominantly renal excretion, makes the drug a good option for the treatment. TPM was found to be effective and well tolerated in many studies conducted in adults and pediatric patients suffering from epilepsy. This review, summarising the main studies in this field, provides an overview of the current knowledge about the relevant pharmacological and clinical information on the efficacy and tolerability of TPM.

The nucleocapsid protein (NC) plays seminal roles in HIV replication, thus representing a major drug target. NC functions rely on its two zinc-fingers and flanking basic residues. Zinc ejectors inhibit NC functions, but with limited specificity. New classes of molecules competing with NC or its viral nucleic acid and enzyme partners are reviewed here.

The emergence of drug resistant strains of important human pathogens has made urgent the necessity of finding new targets and novel antimicrobial agents. One of the most promising targets is FabH. In this review we summarize the progress made in the design of FabH inhibitors and the role played by the 3D-structure of the enzyme in the drug design process.

The combination of electrochemistry coupled on-line to mass spectrometry (EC-MS) forms a powerful analytical technique with unique applications in the fields of drug metabolism and proteomics. In this review the latest developments are surveyed from both instrumental and application perspectives. The limitations and solutions for coupling an electrochemical system to a mass spectrometer are discussed. The electrochemical mimicking of drug metabolism, specifically by Cytochrome P450, is high-lighted as an application with high biomedical relevance. The EC-MS analysis of proteins also has promising new applications for both proteomics research and biomarker discovery. EC-MS has furthermore advantages for improved analyte detection with mass spectrometry, both for small molecules and large biomolecules. Finally, potential future directions of development of the technique are briefly discussed.

Virtual high-throughput screening (vHTS) is a powerful technique for identifying hit molecules as starting points for medicinal chemistry. Numerous successful applications of vHTS have been published using a large variety of methodologies. This review attempts to identify the essential factors for successful virtual screening in the hit identification phase.

The two isoforms of enzyme cyclooxygenase viz. COX-1 and COX-2 play key roles in the metabolism of arachidonic acid. The enzyme COX-2, when over expressed, leads to more production of prostaglandins causing inflammation and it also participates in the propagation of cancer. Therefore, COX-2 becomes the cellular target of a number of chemical entities for the treatment of inflammatory diseases as well as for the chemotherapy of cancer. In the present review, an up to date status of the compounds investigated for COX-2 inhibition has been given so that a collective view of the existing COX-2 inhibitors could be helpful for the design of safer anti-inflammatory drugs. In order to cover the maximum reported COX-2 inhibitors, a unique classification on the basis of the central core of the molecule (carrying mostly the phenyl moieties) has been followed, an outline of which has been given below: Each category of compounds has been discussed with suitable examples giving the IC50 (for COX-2) values and the selectivity towards COX-2 over COX-1 of most potent compounds. Each category of compounds has been discussed with suitable examples giving the IC50 (for COX-2) values and the selectivity towards COX-2 over COX-1 of most potent compounds.

Thyroid stimulating hormone (TSH; also known as thyrotropin), binds cognate receptors on the surface of thyrocytes to regulate proliferation and thyroid hormone synthesis. This unidimensional view of TSH is being transformed as new evidence indicates that TSH acts on adipose tissue. Adipocyte inflammatory responses that predispose to cardiovascular disease may occur in thyroid disorders associated with elevated TSH levels.