Chemistry Reference
In-Depth Information
and dramatically decrease the risk of stroke and overall mortality. HMG-CoA reductase is an important molecular
target of hypolipemic drugs, known as statins, which are effective in the reduction of cholesterol serum levels,
attenuating cholesterol synthesis in-liver by competitive inhibition regarding the substrate HMG-CoA. We focused
on computer-aided molecular design using density functional theory, flexible docking, molecular dynamics as well
as ADMET and synthetic accessibility analyses in order to propose novel potential HMG-CoA reductase inhibitors,
designed by bioiososeric modification which are promising for the treatment of hypercholesterolemia.
We also reported [535] in 2007 virtual screening, molecular interaction field, molecular dynamics with explicit
water solvation, docking, density functional and ADMET properties of novel AChE inhibitors in Alzheimer's
disease (AD). This disease affects approximately 10% of the world's population with 65 years of age, being the
most common form of dementia in adults and is characterized by senile plaquets and cholinergic deficits. Many
drugs currently used for the treatment of AD are based on the improvement of cholinergic neurotransmission
achieved by Acetylcholinestarase (AChE) inhibition, the enzyme responsible for acetylcholine hydrolysis. The
complexes of AChE with inhibitors were computer-aided designed by us. Toxicity and Metabolism predictions,
flexible docking as well as MIF studies were also made. Using the various models discussed above we proposed
novel potential AChE inhibitors for the treatment of Alzheimer's disease.
In 2007 we published the first volume of our Enciclopedia: Current Methods in Medicinal Chemistry and Biological
Physics [542].
In 2008 we performed [536] molecular dynamics, flexible docking, virtual screening, ADMET predictions and
molecular interaction fields studies to design novel potential MAO-B inhibitors. Monoamine oxidase is a
flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative
deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and
MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for
antidepressant, Parkinson's disease and neuroprotecive drugs. Optimizations of the compound, flexible docking and
virtual screening in large databases were done, scored and ranked. Toxicity predictions were performed and the
'Rule of Five' (RO5) were calculated for these proposals. Usage of the various models allowed us to design new
molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.
In 2008 we also reported [537] molecular dynamics, density functional, ADMET predictions, virtual screening,
molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer
therapy. The cyclin-dependent kinases (CDKs) are a class of serine-threonine kinases that are responsible for the
progression of cells through the various phases and transitions of the cell cycle. As the name implies, the activity of
these kinases as well as their subcellular localization and substrate specificity depend upon the presence of a proteic
regulatory subunit called cyclin. We proposed eight novel potential inhibitors of CDK2 which showed interesting
structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for
the treatment of cancer. One of the proposals and one of the drug-like compounds selected by virtual screening
indicated to be promising candidates for CDK2-based cancer therapy.
In 2008 we also investigated a) the use of virtual screening, flexible docking and molecular interaction fields to
design novel HMG-CoA reductase inhibitors for the treatment of hyhpercholesterolemia [538] and b)
pharmacokinetic and pharmacodynamic predictions of novel potential HIV-1 integrase inhibitors [539].
In 2008 we published the second volume of our Enciclopedia: Current Methods in Medicinal Chemistry and
Biological Physics [543].
In 2009 we published research [540] on computer-aided drug design of novel PLA
2
inhibitor candidates for
treatment of snakebites. Phospholipases A
2
(PLA
2
) are enzymes commonly found in snake venoms from Viperidase
and Elaphidae families which are major components thereof. Many plants are used in traditional medicine as active
agents against various effects induced by snakebite. In this work we presented the PLA
2
BthTX-I structure
prediction based on homology modeling. In addition, we performed virtual screening in a large database yielding a
set of potential bioactive inhibitors. A flexible docking program was used to investigate the interaction fields (MIFs)
calculations with the phospholipases model indicating important binding effects. We proposed a theoretically
