Narrow Results

Tumor dissemination and relapse in lung cancer were found to be due to the existence of cancer stem cells. In particular, the $\beta$-catenin pathway is found to be one of the crucial pathways in maintaining the stem-like properties of the cells. Thus, targeting the $\beta$-catenin family of proteins is a significant therapeutic route in the treatment of lung cancer. Therefore, in the present study, a pharmacophore-based drug repurposing approach was accomplished to pinpoint potent $\beta$-catenin inhibitors from the DrugBank database. Primarily, ligand-based pharmacophore hypothesis (AAHHR) was generated using existing $\beta$-catenin inhibitors available in the literature and utilized for library screening. Subsequently, the inhibitory activity of the screened compounds was examined by the hierarchical docking process and the Prime MM-GBSA algorithm. Moreover, quantum chemical calculations and molecular dynamics simulations were executed to analyze the inhibitory effects of the screened hit molecule. The results indicate that hit molecule, DB08047 was found to possess better binding free energy, favorable ligand strain energy, satisfactory pharmacokinetic properties and superior free energy landscape profile. Eventually, the pIC${}_{50}$ values of the lead compounds were predicted by the AutoQSAR algorithm. It is noteworthy to mention that DB08047 was found to possess pyrazole scaffolds which could downregulate $\beta$-catenin pathway and thus facilitate the controlled cell growth/inhibit tumor growth.

Theoretical studies for the bioactive nature of the molecule, 4-aminopyridine 4-aminopyridinium thiocyanate, performed by density function theory (DFT) studies and molecular docking, were simulated by a molecular electrostatic potential surface. Frontier molecular orbitals, molecular properties, and density of state of the spectrum were computed. On account of $E_{\text{HOMO}}$ and $E_{\text{LUMO}}$ showing their notable polarizability and number of reactivity parameters, they were calculated by DFT. The function of new scoring is to calculate the free energy change on binding in docking studies that exploit flexible ligands with macromolecular protein targets that have been evolved and tested. The protein $\beta$-catenin (1JPW) was docked and compared to the standard drug molecule doxorubicin in molecular docking studies. The obtained 4-aminopyridine 4-aminopyridinium crystals revealed the results that confirmed the studied compounds have significant anti-cancer properties.

Familial adenomatous polyposis (FAP) is a familial form of colon cancer caused by mutation of the adenomatous polyposis coli (APC) gene. We investigated the APC mutation and phenotypic spectrum in 172 members of 36 Singapore FAP families. The protein truncation test (PTT) and DNA sequencing were used to screen the entire APC coding region for germline mutations. APC mutations were found in 28 families (78 %). 65 patients tested positive while 63 non-affected members tested negative. The correlation of PTT to clinical diagnosis is therefore 100%, suggesting that PTT is a highly reliable presymptomatic test for FAP. Twenty different APC mutations were identified, eleven of those were novel. All mutations, except one, resulted in the classical colonic phenotype. Interestingly, mutation at codon 332 resulted in attenuated FAP with left-sided predominance of polyps rather than the right. For the eight families without APC mutations, we screened for β-catenin mutation which was shown to be able to substitute for APC mutation in sporadic colorectal cancer. No germline β-catenin mutation was found. Further analysis reveals atypical clinical features such as the co-existence of adenomatous and hyperplastic polyps and other non-FAP associated cancers in these patients. Our results suggest the involvement of other genes and possibly new variants for the polyposis syndrome.