Further Investigations into Rigidity-Activity Relationships in BisQAC Amphiphilic Antiseptics.
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ABSTRACT:
SUBMITTER: Leitgeb AJ
PROVIDER: S-EPMC8322965 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: In a recent paper, a novel W-test for pairwise epistasis testing was proposed that appeared, in computer simulations, to have higher power than competing alternatives. Application to genome-wide bipolar data detected significant epistasis between SNPs in genes of relevant biological function. Network analysis indicated that the implicated genes formed two separate interaction networks, each containing genes highly related to autism and neurodegenerative disorders. Methods: Here we investigate further the properties and performance of the W-test via theoretical evaluation, computer simulations and application to real data. Results: We demonstrate that, for common variants, the W-test is closely related to several existing tests of association allowing for interaction, including logistic regression on 8 degrees of freedom, although logistic regression can show inflated type I error for low minor allele frequencies, whereas the W-test shows good/conservative type I error control. Although in some situations the W-test can show higher power, logistic regression is not limited to tests on 8 degrees of freedom but can instead be tailored to impose greater structure on the assumed alternative hypothesis, offering a power advantage when the imposed structure matches the true structure. Conclusions: The W-test is a potentially useful method for testing for association - without necessarily implying interaction - between genetic variants disease, particularly when one or more of the genetic variants are rare. For common variants, the advantages of the W-test are less clear, and, indeed, there are situations where existing methods perform better. In our investigations, we further uncover a number of problems with the practical implementation and application of the W-test (to bipolar disorder) previously described, apparently due to inadequate use of standard data quality-control procedures. This observation leads us to urge caution in interpretation of the previously-presented results, most of which we consider are highly likely to be artefacts.
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Project description:Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.
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Project description:BackgroundThe epidermal growth factor receptor (EGFR) is a member of the ErbB family that is involved in a number of processes responsible for cancer development and progression such as angiogenesis, apoptosis, cell proliferation and metastatic spread. Malfunction in activation of protein tyrosine kinases has been shown to result in uncontrolled cell growth. The EGFR TK domain has been identified as suitable target in cancer therapy and tyrosine kinase inhibitors such as erlotinib have been used for treatment of cancer. Mutations in the region of the EGFR gene encoding the tyrosine kinase (TK) domain causes altered responses to EGFR TK inhibitors (TKI). In this paper we perform molecular dynamics simulations and PCA analysis on wild-type and mutant (T854A) structures to gain insight into the structural changes observed in the target protein upon mutation. We also report two novel inhibitors identified by combined approach of QSAR model development.ResultsThe wild-type and mutant structure was observed to be stable for 26 ns and 24 ns respectively. In PCA analysis, the mutant structure proved to be more flexible than wild-type. We developed a 3D-QSAR model using 38 thiazolyl-pyrazoline compounds which was later used for prediction of inhibitory activity of natural compounds of ZINC library. The 3D-QSAR model was proved to be robust by the statistical parameters such as r2 (0.9751), q2(0.9491) and pred_r2(0.9525).ConclusionAnalysis of molecular dynamics simulations results indicate stability loss and increased flexibility in the mutant structure. This flexibility results in structural changes which render the mutant protein drug resistant against erlotinib. We report two novel compounds having high predicted inhibitory activity to EGFR TK domain with both wild-type and mutant structure.
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