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

Abstract

Abstract: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 OPEN ACCESSMolecules 2014, 19 10671 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 R 2 = ±0.0106, R 2 ajust = ±0.0125, s = ±0.0234, F (4,11) = ±12.7802, Q 2 = ±0.0088, SEV = ±0.0132, PRESS = ±0.4808 and S PRESS = ±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 (P CaCO2 ), cell permeability Maden Darby Canine Kidney (P MDCK ), skin permeability (P Skin ), plasma protein binding (PPB) and penetration of the blood-brain barrier (C Brain/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.

Validation of Computational Methods Applied in Molecular Modeling of Caffeine With Epithelial Anticancer Activity: Theoretical Study of Geometric, Thermochemical and Spectrometric Data

“…The chemical shift values for hydrogen and carbon atoms of the caffeine molecule can be seen in table 8. In 1 H, The individual analyzed displacements showed better correspondence with the experimental data in HF/3-21G* for H8, DFT/B3LYP -6-311G** for N1-CH 3 , HF/6-31G* and HF/6-31G** for N3-CH 3 and HF/3-21G* for N7-CH 3 .…”

“…However, they point out that 3D modeling, validated from paramagnetic NMR experimental data, is an important tool useful for understanding mechanism, recognition and biomolecular function of complex biological systems. 5 Other different strategies for validation and use of models can be thus cited: 1) Selection of active molecules with potential inhibition of tumors and possible action in the treatment of heart failure with the aid of pharmacophore-based virtual screening, validated from its specificity and sensitivity to active molecules; 6 2) The obtaining new caffeine analogues molecules with epithelial anticancer activity using molecular docking and thus validated by redocking and low RMSD between the experimental crystallographic pose and the calculated one; 7 3) Study with QSAR models, built using PLS and PCR, of new molecules derived from artemisinin, validated from the prediction of the biological activity, followed by comparison with experimental data; 8 4) Validation of the HF/6-31G** method used in the molecular modeling of artemisinin with antimalarial activity, from the correspondence with experimental data of geometric parameters. 9 We have studied the caffeine molecule and analogues using pharmacophore-based virtual screening and statistical analysis and obtained results indicating the caffeine epithelial anticancer potential.…”

Comparison of Density Functional in the Study of Electronic Properties of Artemisinin Derivatives

“…[23][24][25][26][27][28] Desta forma, este trabalho teve como objetivo principal comparar o desempenho dos diversos funcionais de densidade do formalismo DFT, disponíveis no software The General Atomic and Molecular Electronic Structure System (GAMESS), 29 que faz uso de código aberto (software livre), utilizando a artemisinina e alguns de seus derivados (Figura 3) como estudo de caso, na obtenção de propriedades eletrônicas destes compostos. De forma geral, a estrutura dos compostos abordados nesse estudo é de porte médio, sendo, assim, o DFT uma boa escolha para a solução aproximada da equação eletrônica de Schrödinger, já que computacionalmente é menos dispendioso quando comparado a outros como Coupled Cluster 30 e Interação de Configurações e, também, mais eficiente quando comparado ao HF, já que leva em consideração a correlação eletrônica.…”

Nanopartículas Poliméricas Degradáveis Para Carreamento De Proteínas: Com Foco Na Enzima L-Asparaginase

“…A ANVISA define como medicamentos fitoterápicos os obtidos com emprego exclusivo de matérias-primas ativas vegetais e que tenham sido testados em estudos clínicos (BRASIL, 2014…”