Current Bioactive Compounds - Volume 5, Issue 2, 2009

This issue is aimed for anyone who is interested or works with current theoretical methods in medicinal chemistry, with particular interest in chemoinformatics and bioinformatics for many therapeutic purposes. This issue attempts to convey something of the fascination of working in the multidisciplinar field of Medicinal Chemistry, which overlap knowledge of chemistry, physics, biochemistry, biology and pharmacology. Alpha- and beta-glucosidases are postulated to be very attractive therapeutic targets since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo- or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, AIDS, metastatic cancer and lysosomal storage diseases. In Chapter 1 comparative modeling and bioinformatic procedures have been reported to suggest the highest affinity of the human enzyme with the rat intestinal sucrase, when compared to other homolog proteins commonly used in activity assays. Consequently, the authors have built and validated a 3D model for this rat alpha-glucosidase, and additionally performed docking simulations of well-known glucosidase inhibitors as well as pharmacophore modeling and molecular interaction field studies in order to establish the most relevant structural features of inhibitors and enzyme as well as for inhibitory activity. Using this mixed methodology they have explained activities of reported inhibitors as well as discussed about key alpha-glucosidase residues in the active site, in order to design novel pharmaceuticals candidates. The high frequency of contamination by herbicides suggests the need for more active and selective herbicides. Glyphosate is the active component of one of the top-selling herbicides, which is also a potent EPSP synthase inhibitor. In this line, molecular modeling studies using molecular dynamics simulations and molecular docking techniques have been described in Chapter 2 leaving to the understanding of the interaction of glyphosate and its analogs with the wild type enzyme and Gly96Ala mutant EPSP synthase. Findings indicate some key points for the designing of new selective glyphosate derivates. Alzheimer's disease has become one of the most serious healthcare problems nowadays, where age is clearly the major risk factor. The pathology of the disease is characterized by the formation of senile plaques outside of the neurons, which are composed, predominantly, by the beta-amyloid peptide. Considering that beta-secretase is an aspartyl protease involved in the cleavage of the amyloid precursor, the first step required for the formation of the beta-amyloid, it becomes an attractive therapeutic target for drug design. In Chapter 3, a virtual screening approach based on flexible docking was applied in order to identify potential inhibitor candidates of beta-secretase, since the docking method used here showed to be able to reproduce the binding modes of crystallographic complexes. Overall, results here obtained suggest that novel potential beta-secretase inhibitors proposed could be a promising pharmaceutical for the Alzheimer's disease treatment. The enzyme reverse transcriptase (RT) is essential in the replication of human immunodeficiency virus (HIV). Nonnucleoside reverse transcriptase inhibitors (NNRTI's) are a promising class of anti-HIV drugs, which block the chemical step of DNA polymerization reaction by binding at the allosteric site of RT, leading to a viral suppression. A major limitation to the success of therapy with NNRTIs is the rapid development of drug-resistant mutants. In Chapter 4 the usage of molecular modeling, virtual screening, flexible docking, molecular interaction field, pharmacophoric alignment, toxicity predictions, and molecular dynamics simulations has been reported in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over K103N RT enzyme, which is the most common mutation to emerge.

α- and β-glucosidases are postulated to be a very attractive therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo- or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, AIDS, metastatic cancer and lysosomal storage diseases. α-Glucosidases can be divided into two groups, family I and family II, and the appropriate choice of the homologue enzyme to structure-based drug design purposes could prove to be successful in the development of new pharmaceuticals. In this work, we have found the highest identity of the human enzyme with the rat intestinal sucrase, when compared to other homologue proteins commonly used in biological assays, such as Saccharomyces cerevisiae α-glucosidase. Consequently, we have built and validated a 3D model for this rat enzyme, and additionally performed docking simulations of well-known glucosidase inhibitors as well as pharmacophore modeling and molecular interaction fields studies in order to establish the most relevant structural features of inhibitors and enzyme for inhibitory activity. Using this mixed methodology we have proposed how the reported inhibitors may interact at molecular level as well as discussed the role of key α-glucosidase residues in the active site, in order to design novel proposals of inhibitors.

The high frequency of contamination by herbicides suggests the need for more active and selective herbicides. Glyphosate is the active component of one of the top-selling herbicides, which is also a potent EPSP synthase inhibitor. That is a key enzyme in the shikimic acid pathway, which is found only in plants and some microorganisms. Thus, EPSP synthase is regarded as a prime target for herbicides. In this line, molecular modeling studies using molecular dynamics simulations and molecular docking techniques were performed to understand the interaction of glyphosate and its analogs with the wild type enzyme and Gly96Ala mutant EPSP synthase. Our findings indicate some key points for the designing new selective glyphosate derivates.

Alzheimer's disease has become one of the most serious healthcare problems nowadays, where age is clearly the major risk factor. The pathology of the disease is characterized by the formation of senile plaques outside the neurons, which are composed, predominantly, by the β-amyloid (Aβ) peptide. Considering that β-secretase is an aspartyl protease involved in the cleavage of the amyloid precursor, the first step required for the formation of Aβ, becomes an attractive therapeutic target for drug design. A virtual screening approach based on flexible docking was applied in order to identify potential inhibitor candidates of β-secretase, since the docking method used here showed to be able to reproduce the binding modes of crystallographic complexes. After validation, ten potential inhibitors were selected and evaluated with respect to the analysis of toxicological groups. The most promising inhibitor candidate was analyzed in a molecular dynamics trajectory to reinforce, theoretically, the potential inhibitory activity. Overall results obtained here suggest that this novel potential β-secretase inhibitor could be a promising pharmaceutical for the Alzheimer's disease treatment.

The enzyme reverse transcriptase (RT) is essential in the replication of human immunodeficiency virus (HIV). Non-nucleoside reverse transcriptase inhibitors or NNRTI's are a promising class of anti-HIV drugs, which block the chemical step of DNA polymerization reaction by binding at the allosteric site of RT, leading to a viral suppression. A major limitation to the success of therapy with NNRTIs is the rapid development of drug-resistant mutants. In this work we have used molecular modeling, virtual screening, flexible docking, molecular interaction field, pharmacophoric alignment, toxicology predictions, and molecular dynamics simulations in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over K103N RT enzyme, which is the most common mutation to emerge.

Tuberculosis (TB) remains one of the most deadly infectious diseases in the world, killing about 2 million people per year, and mostly affecting the world's poorest population. The length of current regimens for treatment of TB is long (6-9 months) with a high pill burden. Furthermore, one third of the world population is infected, though asymptomatically, with latent TB and is at risk of developing active TB disease during their lifetime. The current TB epidemic is fuelled by co-infection with HIV, the rise of multidrug-resistant strains, and the ability of the bacterium to become dormant in the lungs and to be reactivated in immunocompromised people. Despite medical advances over the last decades, including the genomic and proteomic revolution, TB still is a highly neglected disease. However, the search for new TB drugs is gaining momentum. Several efforts are underway to develop new drugs, within the academia, the pharmaceutical industry and as public private partnerships. This review will provide a chemical, biological and pharmacological overview of the six drug candidates currently in clinical development. Moxifloxacin (fluoroquinolone), TMC207 (diarylquinoline), PA-824 and OPC-67683 (nitroimidazoles), LL3858 (pyrrole) and SQ109 (ethambutol analogue) will be presented.

Searching for bioactive molecules from natural source represents an attractive strategy. Natural bioactive molecules form the backbone of modern therapeutics. For that reason the glycolipoprotein extract (G-90) from tissue homogenate of earthworm Eisenia foetida represents a valuable source of bioactive molecules. The molecules in this preparation exhibit many biological characteristics, useful in different biological processes. This extract showed interaction with biological materials from evolutionary more developed species, such as serums, erythrocytes, normal and transformed cells in culture from different origin. The numerous biological activities in vitro and in vivo, such as mitogenicity, anticoagulation, fibrinolysis, bacteriostasis, antioxidation, were detected in G-90. In therapeutic concentrations G-90 was not toxic, allergenic, mutagen or carcinogen. G-90 protected cells in culture from oxidative damage, caused by hydrogen peroxide. It is capable to stimulate the cellular immune system. As fibrinolytic and anticoagulative agent it can participate in active maintenance of homeostasis. G-90 has the ability to stimulate the synthesis of growth factors and helps in tissue regeneration. It stimulates proliferation of fibroblasts and epithelial cells, as well as their differentiation. Accordingly, G- 90 is a valuable mixture of bioactive molecules from natural source, which could be very useful in human and veterinary medicine.

Betulinic acid, a naturally occurring pentacyclic triterpenoid was found in many plants. It has been isolated with considerable success from birch bark. Apart from its isolation from plants, betulinic acid is also synthesized from betulin by different methods. It exhibits broad range of biological activities such as anticancer, antimalarial, anti-HIV, antiviral and immunomodulator activity. Anticancer property of this molecule is attributed to its ability to induce apoptosis and inhibit angiogenesis. It also inhibits topoisomerase and aminopeptidase acitvity. It induces apoptosis by direct effect on mitochondria through cleavage of caspase-8 and caspase-3 and activates nuclear factor-kappa-B (NF-kappa-B), which is a key regulator of stress-induced transcriptional activation. Activation of proapoptotic mitogen-activated protein kinases (MAPKs) and generation of reactive oxygen species (ROS) also induce apoptosis in cancerous cells. Betulinic acid is found to exhibit synergistic effect with radiation therapy and cytotoxic drugs such as vincristine, doxorubicin, taxol, cisplatin etc. Betulinic acid acts as a chemosensitizer for anticancer drug treatment in chemoresistant cancer cell lines. Studies have been performed on the structure- activity relationship of betulinic acid for anticancer activity. The three-ring skeleton (A, B and C rings) and C-28 carboxylic acid are important in eliciting anticancer activity. This phytochemical constituent puts forward new areas of research and development. It would be interesting to see its potential as a potent cytotoxic agent.