Current Drug Targets - Volume 11, Issue 3, 2010

Development of a successful drug is the result of a combination of biological activity and drug-like properties. Both features can be estimated by in silico methodologies in the initial stages of drug discovery and development. Application of molecular docking simulations to scan a library of small-molecules to identify a potential inhibitor for a protein target is a methodology referred to as structure-based virtual screening (SBVS). T Read More

This paper provides an overview of computational de novo protein design methods, highlighting recent advances and successes. Four protein systems are described that are important targets for drug design: human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases. Target areas for drug design for each protein are described, along with known inhibitors, Read More

Cell cycle deregulation is one of the first steps that transform normal cells into tumor cells. CDKs are a family of proteins devoted to controlling cell cycle entry, progression and exit. Studies from animal models show a tissuespecific essentiality of the single CDKs. In cancer cells, mis-regulation of CDK function is a common event. For this reason the pioneer compound Flavopiridol was developed and many new drugs are currently Read More

Poor therapeutic outcomes and serious side effects, together with acquired resistance to multiple drugs, are common problems of current cancer therapies. Therefore, there is an urgent need for new cancer-targeted drugs, which has led (inter alia) to the development of molecules that can specifically inhibit cyclin-dependent kinases (CDKs). In addition to their cell cycle regulatory functions, CDKs, especially CDK7 and CDK9, Read More

A significant number of drugs and drug candidates in clinical development are halogenated structures. For a long time, insertion of halogen atoms on hit or lead compounds was predominantly performed to exploit their steric effects, through the ability of these bulk atoms to occupy the binding site of molecular targets. However, halogens in drug - target complexes influence several processes rather than steric aspects alone. Fo Read More

Since 2003, highly pathogenic H5N1 influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. At present, there are only three licensed anti-Influenza drugs namely Relenza (Zanamivir - ZMV), Tamiflu (Oseltamivir - OTV) and Amantadine/Rimantadine. The latter targets the M2 ion channel whereas the other compounds target neuraminidase (NA) and were Read More

Molecular docking is a simulation process where the binding of a small molecule is identified in the structure of a protein target. There are several different computational approaches to solve this problem. Here it is described recent developments in application of evolutionary algorithms to molecular docking simulations. Evolutionary algorithms are classified as a group of computational techniques based on the concepts of Read More

Z-DNA, the alternative form of double-stranded DNA involved in a variety of nucleotide metabolism, is recognized and stabilized by specific Z-DNA binding proteins (ZBPs). Three ZBPs known in vertebrates --ADAR1, DAI and PKZ-- modulate innate immunity, particularly, the IFN-induced immune response. The E3L protein of vaccinia virus appears to compete with the host ZBP for Z-DNA binding, thereby suppressing the host imm Read More

RNA interference (RNAi) is a phenomenon of sequence-specific gene silencing in mammalian cells and its discovery has lead to its wide application as a powerful tool in post-genomic research. Recently, short interfering RNA (siRNA), which induces RNAi, has been experimentally introduced as a cancer therapy and is expected to be developed as a nucleic acid-based medicine. Selection of appropriate gene targets is an important Read More

Valproic acid (VPA) has been used for epilepsy treatment since the 1970s. Recently, it was demonstrated that it inhibits histone deacetylases (HDAC), modulates cell cycle, induces tumor cell death and inhibits angiogenesis in various tumor models. The exact anticancer mechanisms of VPA remains unclear, but HDAC inhibition, extracellular-regulated kinase activation, protein kinase C inhibition, Wnt-signaling activation, prot Read More

Thrombus formation at a site of arterial injury (eg, rupture of an atherosclerotic plaque in a carotid artery), a crucial step in the pathogenesis of cerebral ischemia, is initiated by the adhesion of platelets to the arterial wall. In vivo, activated platelets release adenosine diphosphate (ADP), whose binding to the platelet P2Y12 receptor elicits progressive and sustained platelet aggregation. As a result, this receptor has been a Read More