Computational Approaches Towards Kinases as Attractive Targets for Anticancer Drug Discovery and Development.

BACKGROUND: One of the major goals of computational chemists is to determine and develop the pathways for anticancer drug discovery and development. In recent past, high performance computing systems elicited the desired results with little or no side effects. The aim of the current review is to evaluate the role of computational chemistry in ascertaining kinases as attractive targets for anticancer drug discovery and development. METHODS: Research related to computational studies in the field of anticancer drug development is reviewed. Extensive literature on achievements of theorists in this regard has been compiled and presented with special emphasis on kinases being the attractive anticancer drug targets. RESULTS: Different approaches to facilitate anticancer drug discovery include determination of actual targets, multi-targeted drug discovery, ligand-protein inverse docking, virtual screening of drug like compounds, formation of di-nuclear analogs of drugs, drug specific nano-carrier design, kinetic and trapping studies in drug design, multi-target QSAR (Quantitative Structure Activity Relationship) model, targeted co-delivery of anticancer drug and siRNA, formation of stable inclusion complex, determination of mechanism of drug resistance, and designing drug like libraries for the prediction of drug-like compounds. Protein kinases have gained enough popularity as attractive targets for anticancer drugs. These kinases are responsible for uncontrolled and deregulated differentiation, proliferation, and cell signaling of the malignant cells which result in cancer. CONCLUSION: Interest in developing drugs through computational methods is a growing trend, which saves equally the cost and time. Kinases are the most popular targets among the other for anticancer drugs which demand attention. 3D-QSAR modelling, molecular docking, and other computational approaches have not only identified the target-inhibitor binding interactions for better anticancer drug discovery but are also designing and predicting new inhibitors, which serve as lead for the synthetic preparation of drugs. In light of computational studies made so far in this field, the current review highlights the importance of kinases as attractive targets for anticancer drug discovery and development.

13C-1H coupling constants as a conformational tool for structural assignment of quinic and octulosonic acid.

A complete set of NMR coupling constants (1JC-H, 2JC-H, 3JC-H, and 3JH-H) were calculated for the eight stereoisomers of quinic acid, at the B3LYP/6-311G(d,p)/PCM(methanol) level of theory. The Fermi contact term of the coupling constants was computed with a modified, uncontracted, version of the 6-311G(d,p) basis set, with additional tight polarization functions. 1H and 13C NMR chemical shifts were determined at the same level using the gauge-invariant atomic orbital (GIAO) method. The magnitude of the spin-spin coupling constants was found to be affected by the orientation (axial or equatorial) of the coupling proton and the orientation of the hydroxy group on the coupling carbon, whereas the chemical shifts depend on the presence or absence of electron-withdrawing hydroxy groups attached to the carbon atoms involved. Graphical Abstract Nuclear magnetic resonance coupling constants, computed with density functional theory, can be used to differentiate and identify the different stereoisomers of quinic acid.

Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus.

Cytotoxic and antiviral potential of ivermectin and ribavirin was evaluated. Cytotoxicity was checked on chick primary fibroblast cell line through MTT assay. Antiviral potential was determined against Newcastle disease virus on 9-day old chicken embryos. Six different concentrations (200, 100, 50, 25, 12.5 and 6.25µg/ml) of both the drugs were evaluated. The 100µg/ml concentration of ivermectin and higher were cytotoxic. The 25µg/ml concentration of ribavirin and higher were cytotoxic. Comparison of ivermectin and ribavirin showed that ivermectin was safe at 50µg/ml and lower concentrations. Ribavirin was protective for cell at 12.5µg/ml and 6.25µg/ml only. Comparison of antiviral activity indicated that ivermectin has strong antiviral potential at 100µg/ml and higher but same concentrations were cytotoxic. Ribavirin showed strong antiviral potential at all concentrations.

DNMT3B7 expression promotes tumor progression to a more aggressive phenotype in breast cancer cells.

Epigenetic changes, such as DNA methylation, have been shown to promote breast cancer progression. However, the mechanism by which cancer cells acquire and maintain abnormal DNA methylation is not well understood. We have previously identified an aberrant splice form of a DNA methyltransferase, DNMT3B7, expressed in virtually all cancer cell lines but at very low levels in normal cells. Furthermore, aggressive MDA-MB-231 breast cancer cells have been shown to express increased levels of DNMT3B7 compared to poorly invasive MCF-7 cells, indicating that DNMT3B7 may have a role in promoting a more invasive phenotype. Using data gathered from The Cancer Genome Atlas, we show that DNMT3B7 expression is increased in breast cancer patient tissues compared to normal tissue. To determine the mechanism by which DNMT3B7 was functioning in breast cancer cells, two poorly invasive breast cancer cell lines, MCF-7 and T-47D, were stably transfected with a DNMT3B7 expression construct. Expression of DNMT3B7 led to hypermethylation and down-regulation of E-cadherin, altered localization of ß-catenin, as well as increased adhesion turnover, cell proliferation, and anchorage-independent growth. The novel results presented in this study suggest a role for DNMT3B7 in the progression of breast cancer to a more aggressive state and the potential for future development of novel therapeutics.

Smokeless tobacco use among adult patients who visited family practice clinics in Karachi, Pakistan.

BACKGROUND: Use of smokeless tobacco (SLT) is significantly associated with poor oral health and cancers. The objectives of this study were to estimate the proportion of use and the knowledge about SLT in relation to oral cancer and its differentials by socio-demographic and patient's diagnostic categories. This study also aimed to assess the SLT user's attitude and practices for its use. METHODS: In a cross-sectional study, 502 adult patients (> or =15 years) were randomly interviewed in family practice clinics in Karachi, Pakistan. SLT use was considered as usage of any of the following: betel quid (paan) with tobacco, betel nuts with tobacco (gutkha), and snuff (naswar). RESULTS: Overall, 52.4% subjects had used SLT at least in one form. More males were using SLT than females (P = 0.03). Similarly, higher proportion of patients with gastro-intestinal diseases were using SLT compared with other diagnostic categories (P = 0.004). Knowledge about the oral carcinogenic effect of SLT was higher among men and those who had schooling of >10 years (P < 0.001). This knowledge was also higher in patients with non-communicable and infectious diseases. Among SLT users, 31.3% tried to quit this habit but failed. The majority of users started using SLT before the age of 15 years; 40.2% and 30.8% started after being inspired by media advertisements and friends/peer pressure, respectively. CONCLUSIONS: In this study, over half of the patients were using SLT in various forms and had poor knowledge about its hazards. We suggest that there is a need for socially and culturally acceptable educational and behavioral interventions for control of SLT usage.