Current Bioactive Compounds - Volume 9, Issue 1, 2013

p38α MAPK, initially discovered as a target for inhibition of proinflammatory cytokines, has been linked to several CNS disorders in preclinical animal models of CNS diseases, including Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia and neuropathic pain. Here we describe pharmacophore and similarity-based virtual screenings of more than 18.3 million compounds based on correlation between the specific binding mode and activity of different types of p38α MAPK inhibitors and present novel potential p38α MAPK inhibitors.

Alzheimer's Disease (AD) is the major cause of senile dementia, flawing out 10% of 65 years old population and 50% of 85 years old, globally. The major physiopathology of AD is the deposition of extracellular neuritic plaques in memory related areas of the brain. These plaques are composed of the β-amyloid peptide resulting from the amyloidogenic pathway, that starts with the β-secretase enzyme. BACE-1 (β-secretase 1) is considered one of the most promising treatments of the disease. In this work, different molecular modeling and drug design techniques were used to design novel inhibitors of BACE-1, starting from structures available in the Protein Data Bank. The results obtained from virtual screening of compound libraries lead to 28 promising compounds, which were then evaluated by toxicity prediction, pharmacokinetic properties and analysis of the binding modes in the catalytic site, resulting in 10 compounds with high theoretical inhibition potential.

An intracellular hallmark of Alzheimer's Disease (AD) is accumulation of hyperphosphorylated tau as paired helical filaments (PHF). A significant advance in understanding the behavior of tau occurred when it was reported that VQIVYK hexapeptide motif is responsible for initiating the process of aggregation. In the last years, a great number of Tau aggregation inhibitors have been developed, including flavonoids. However, the binding mode of these potential drugs is not well established. In this work, the behavior and conformational stability of the Tau hexapeptide306VQIVYK311 were investigated in the presence of two known flavonoid inhibitors using Molecular Interaction Fields (MIFs), pharmacophore perception and molecular dynamics (MD) simulations. We have also proposed a likely binding mode for such inhibitors with the hexapeptide, which agrees with experimental data and is able to explain structure-activity relationships between different flavonoids.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by marked atrophy of cortex and loss of cortical and subcortical neurons. At least two Casein Kinase 1 isoforms have been implicated in the pathogenesis of AD. The ligand-based virtual screening (LBVS) technique uses the information of a set of actives, focusing on the activity of this group of molecules against the desired target. Generally, this type of technique is used when there is no information on the three dimensional structure of the target. However, the use of LBVS allied with three-dimensional information of the protein binding site provides a more accurate screening, since the information of the active site is taken into account during the analysis of results.

The role of various structural features, namely basic scaffolds and substituents of small molecule inhibitors of the self-assembly of amyloid-beta (Aβ) peptide, a key process in Alzheimer's disease, is described. The literature analysis in this update extends to the past 5 years, thus the past 15 year period is covered. In addition, while our previous review was limited to anti-fibril agents the current update includes compounds with a major profile in oligomer inhibition as well, and covers inhibitors of the broadly defined Aβ self-assembly. Basis sets of 507 fibrillogenesis inhibitors and 154 oligomer formation inhibitors were surveyed and a chemical map of the inhibitors is provided highlighting the most common substituents that appear in these compounds.

In recent years, considerable research efforts have focused on the role of serotonin in various pathological states, as well as on the identification of the respective serotonin receptors involved. Among serotonin receptors, 5-HT6R is the most recently discovered sub-class. Despite the development of multiple selective ligands, the functional role of this receptor has thus far remained elusive. Available in vitro and in vivo evidence indicates that 5-HT6 receptor antagonists can produce promnesic or antiamnesic effects in a variety of contexts, including memory formation, age-related cognitive impairments, and memory deficits associated with conditions such as schizophrenia, Parkinson's disease, and Alzheimer's disease. Recent progress in the understanding of the 5-HT6 receptor and its ligands includes a suggested constitutive activity for the receptor, development of a number of multimodal small molecule ligands, and re-classification of many selective antagonists as pseudo-selective compounds. In light of these findings, the observed pharmacological effects produced by 5-HT6R ligands are now properly assigned to a spectrum of related biological targets, rather than to an individual receptor.