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

Molecules

Josinete B. Vieira³  Francinaldo S. Braga³  Cleison C. Lobato³  César F. Santos³  Josivan S. Costa³  José Adolfo H. M. Bittencourt²  Davi S. B. Brasil³  Jocivânia O. Silva¹  Lorane I. S. Hage-Melim³  Williams Jorge C. Macອo³  José Carlos T. Carvalho¹ 

[1] Postgraduate Program in Pharmaceutical Sciences, Federal University of Amapá, Rod JK Km 2, Macapá, Amapá 68902-280, Brazil; E-Mails:;Laboratory of Drug Research, School of Pharmaceutical Sciences, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil; E-Mail:;Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil; E-Mails:

关键词: artemisinin;    anticancer activity;    molecular modeling;    B3LYP/6-31G**;    QSAR;   

DOI  :  10.3390/molecules190810670

来源: mdpi

【 摘 要 】

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 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 R² = ±0.0106, R²_ajust = ±0.0125, s = ±0.0234, F_(4,11) = ±12.7802, Q² = ±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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.