RESUMEN
Polyketide synthase 13 (Pks13) is one of prominent targets to treat Mycobacterium tuberculosis (Mtb). In the presentstudy, pharmacophore features for Pks13, including two hydrogen bond donors, one hydrogen bond acceptor, and onehydrophobic feature, were built using a novel Pks13 inhibitor, TAM16. The pharmacophore features were then usedto perform virtual screening on ZINC database to identify small molecules of Pks13 inhibitors. The obtained virtualhits of 107 small molecules were subjected to molecular docking studies employing iDock software to reveal theirbinding orientation to Pks13. Furthermore, four best hits, each bound to Pks13, were submitted to 40-ns moleculardynamics simulation to explore their conformational changes throughout simulation. The result showed that all hitcompounds, i.e., Lig79/ZINC09281113, Lig94/ZINC09584070, Lig95/ZINC09209668, and Lig97/ZINC09216165,have better stabilities than that of TAM16 as indicated by their lower values of root-mean-square-deviation and rootmean-square-fluctuation. In a similar way, prediction of binding free energy using molecular mechanics Poisson–Boltzmann Surface Area method showed that all hit compounds have lower binding free energies than that of TAM16,indicating their potential as novel compounds of Pks13 inhibitors.
RESUMEN
One of the most common triggers of breast cancer is over-expression of estrogen receptor alpha (ERα). Long-termtherapy of tamoxifen, an ERα antagonist, can reduce patient’s quality of life because of its side effects. In the previousstudy, 2’,4’-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) was isolated as an active compound from theEugenia aquea leaves that is responsible for breast cancer treatment with positive ERα, however, the potency is lowerthan tamoxifen. The aim of this study is to find the best-modified chalcone that binds well with the ERα. Drug designapproaches used in this study were Structure-Based (Autodock 4.1) and Ligand-Based (LiganScout 4.1). Prediction ofabsorption, distribution, and toxicity parameters was employed using preADMET and Toxtree. Interactions betweentamoxifen and ERα were determined and the differences in the binding modes between tamoxifen and chalcones wereobserved. Modifina3 had pharmacophore fit score value of 76.42% and the molecular docking studies showed thelowest free energy binding (∆G) of −11.07 kcal/mol while tamoxifen of −10.15 kcal/mol. Modifina3 had absorptionand distribution properties with the percentage human intestinal absorption of 95.90%, CaCO2 of 46.95%, and proteinplasma binding of 93.55%. Toxicity prediction of Modifina3 was categorized in class III and risk assessment requirescompound specific toxicity data. These results suggest that Modifina3 has the potency to be a novel therapeuticcompound for potent ERα inhibitor targeted breast cancer.
RESUMEN
Apurinic/apyrimidinic endonuclease 1 (APE1) is an enzyme responsible for the initial step in the base excision repair pathway and is known to be a potential drug target for treating cancers, because its expression is associated with resistance to DNA-damaging anticancer agents. Although several inhibitors already have been identified, the identification of novel kinds of potential inhibitors of APE1 could provide a seed for the development of improved anticancer drugs. For this purpose, we first classified known inhibitors of APE1. According to the classification, we constructed two distinct pharmacophore models. We screened more than 3 million lead-like compounds using the pharmacophores. Hits that fulfilled the features of the pharmacophore models were identified. In addition to the pharmacophore screen, we carried out molecular docking to prioritize hits. Based on these processes, we ultimately identified 1,338 potential inhibitors of APE1 with predicted binding affinities to the enzyme.