Lorane I. S. Hage-Melim

Computer-aided Drug Design of Novel PLA2 Inhibitor Candidates for Treatment of Snakebite

Abstract Phospholipases A2 (PLA2) are enzymes commonly found in snake venoms from Viperidae and Elaphidae families, which are major components thereof. Many plants are used in traditional medicine as active agents against various effects induced by snakebite. This article presents the PLA2 BthTX-I structure prediction based on homology modeling. In addition, we have performed virtual screening in a large database yielding a set of potential bioactive inhibitors. A flexible docking program was used to investigate the interactions between the receptor and the new ligands. We have performed molecular interaction fields (MIFs) calculations with the phospholipase model. Results confirm the important role of Lys49 for binding ligands and suggest three additional residues as well. We have proposed a theoretically nontoxic, drug-like, and potential novel BthTX-I inhibitor. These calculations have been used to guide the design of novel phospholipase inhibitors as potential lead compounds that may be optimized for future treatment of snakebite victims as well as other human diseases in which PLA2 enzymes are involved.

Protective Effect of Schizolobium parahyba Flavonoids Against Snake Venoms and Isolated Toxins

Four compounds (isoquercitrin, myricetin-3-O-glucoside, catechin and gallocatechin) were isolated from lyophilized aqueous extract of Schizolobium parahyba leaves by chromatography on Sephadex LH-20, followed by semipreparative HPLC using a C-18 column, and identified by 1H and 13C NMR. The compounds were then, tested against hemorrhagic and fibrinogenolytic activities of Bothrops crude venoms and isolated metalloproteinases. The inhibitors neutralized the biological and enzymatic activities of Bothrops venoms and toxins isolated from B. jararacussu and B. neuwiedi venoms. The results showed that gallocatechin and myricetin-3-O-glucoside are good inhibitors of hemorrhagic and fibrinogenolytic activities of metalloproteinases, respectively. Gallocatechin also inhibited the myotoxic activity of both B. alternatus venom and BnSP-6 (Lys49 PhospholipaseA2 from B. neuwiedi). Circular dichroism and docking simulation studies were performed in order to investigate the possible interaction between BnSP-6 and gallocatechin. This is the first time these compounds and their anti-ophidian properties are reported for S. parahyba species. Forthcoming studies involving X-ray co-crystallization, will be of great importance for the development of new therapeutic agents for the treatment of ophidian accidents and for the better understanding of the structure/function relationship of venom toxins.

A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity

The Density Functional Theory (DFT) method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R2 = ±0.0106, R2ajust = ±0.0125, s = ±0.0234, F(4,11) = ±12.7802, Q2 = ±0.0088, SEV = ±0.0132, PRESS = ±0.4808 and SPRESS = ±0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set) with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA), cellular permeability (PCaCO2), cell permeability Maden Darby Canine Kidney (PMDCK), skin permeability (PSkin), plasma protein binding (PPB) and penetration of the blood-brain barrier (CBrain/Blood), and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers.

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis, New Perspectives for Pharmacological Treatment

Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimers disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increase to 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimers disease, emphasizing the research and development of new therapeutic approaches.

Phospholipase A2 inhibitors isolated from medicinal plants: alternative treatment against snakebites.

Many plants are used in traditional medicine as active agents against various effects of snake bites. Phospholipase A2 enzymes are commonly found in venoms of snakes of the Viperidae and Elaphidae families, which are their main components. This article presents an overview of inhibitors isolated from plants, which show antiophidian properties.

Cannabinoid Type 1 Receptor (CB1) Ligands with Therapeutic Potential for Withdrawal Syndrome in Chemical Dependents of Cannabis sativa

Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2‐n‐butyl‐5‐n‐pentylbenzene‐1,3‐diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome.

Computational Medicinal Chemistry to Design Novel Phosphoinositide 3- Kinase (PI3K) Alpha Inhibitors in View of Cancer

Phosphoinositide 3-kinase (PI3K) is an enzyme involved in the signaling and control of essential cell functions with respect to receptor tyrosine kinase (RTK), for which they are activated. PI3K is involved in some types of cancers in humans, as has been observed in breast, hepatocellular, and colorectal, where, in this latter one, it was only the gene whose mutation was showed. When this gene mutation occurs, overstimulation of this pathway may occur, resulting in an overexpression of tyrosine kinase pathway and inactivation of the Phosphatase and tensin homolog (PTEN), which is a tumor suppressor most frequently deregulated in cancer. The present study aimed to investigate the known inhibitors of PI3K-alpha, deposited in databases such as Binding DB and PDB, in order to draw a profile of physicochemical and pharmacokinetic properties of the most active inhibitors for this enzyme. From this, nine proposals of potential new PI3K inhibitors were developed, which were evaluated with respect to pharmacokinetic and physicochemical properties, activity and toxicity predictions, as well as synthetic accessibility. The results suggest that some of the proposals may be promising new PIK3 inhibitors, containing drug properties.

UM PROTOCOLO SIMPLES E EFICIENTE PARA A REAÇÃO DE KNOEVENAGEL DE BENZILIDENEMALONONITRILES E AVALIAÇÃO DA ATIVIDADE LARVICIDA EM AEDES AEGYPTI

Mosquitoes of the genus Aedes are responsible for dengue, yellow fever, chikungunya and Zika. Although important advances have emerged in the development of alternative methods for mosquito control, chemical insecticides remain a vital part of integrated control programs. In this paper were synthetized benzylidenemalononitrile derivatives in good yields (71-99%) using only water and glycerol at room temperature. A study of the larvicidal activity between benzylidenemalononitriles showed that the compound 2e (R= 4-Cl) possesses excellent larvicidal activity (LC50 and LC90 of 9.42 and 15.02, respectively at 24 h). A study of molecular docking was applied to identify the type of interaction of compound 2e with binding sites at the enzyme acetylcholinesterase. The profile of the interaction showed a score 48.9795 with five bonds at three different amino acids.Mosquitoes in the genus Aedes are responsible for the four important human disease viruses, such as, dengue, yellow fever, chikungunya and Zika. Although important advances have emerged in the development of alternative measures for mosquito control, chemical insecticides still remain a vital part of integrated control programs. In this sense, a set of benzylidenemalononitriles were synthetized in very good yields (99-71%), using only water and glycerol at temperature room. A comparative study of the larvicidal activity between benzylidenemalononitriles showed that the 2g (R= 4-Cl) compounds possess much better larvicidal activity (LC50 and LC90 of 9.42 and 15.02, respectively at 24h). Study of molecular docking was applied to identify the mode iteration of compound 2g with binding site at the enzyme acetylcholinesterase, the profile of interaction showed a score 48.9795, with five bonds in three different amino acids.