In Silico Design of Novel Piperazine-Based mTORC1 Inhibitors Through DFT, QSAR and ADME Investigations
El Mehdi Karim,
Oussama Abchir,
Hassan Nour,
Ossama Daoui,
Souad El Khattabi,
Farhan Siddique,
M’Hammed El Kouali,
Mohammed Talbi,
Abdelkbir Errougui,
Samir Chtita
Affiliations
El Mehdi Karim
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Oussama Abchir
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Hassan Nour
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Ossama Daoui
Laboratory of Engineering, Systems and Applications, National School of Applied Sciences, Sidi Mohamed Ben Abdellah-Fez University, Fez P.O. Box 72, Morocco
Souad El Khattabi
Laboratory of Engineering, Systems and Applications, National School of Applied Sciences, Sidi Mohamed Ben Abdellah-Fez University, Fez P.O. Box 72, Morocco
Farhan Siddique
Departement of Farmaceutical Chemistry, Faculty of Pharmacy, Bahahuddian Zakariya University, Multan 60800, Pakistan
M’Hammed El Kouali
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Mohammed Talbi
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Abdelkbir Errougui
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Samir Chtita
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco
Mammalian target of rapamycin complex 1 (mTORC1) is an important and promising alternative biological target for the treatment of different types of cancer including breast, lung and renal cell carcinoma. This study contributed to the development of mathematical models highlighting the quantitative structure-activity relationship of a series of piperazine derivatives reported as mTORC1 inhibitors. Various molecular descriptors were calculated using Gaussian 09, Chemsketch, and ChemOffice software. The density funcional theory (DFT) method at the level B3LYP/6-31G+(d, p) was applied to determine the structural, electronic and energetic parameters associated with the studied molecules. The predictive ability of the built models, which is obtained by two methods (MLR and MNLR), showed that the built models are statistically significant. The QSAR modeling results revealed that the six molecular descriptors of lowest unoccupied molecular orbital energy (ELUMO), electrophilicity index (ω), molar refractivity (MR), aqueous solubility (Log S), topological polar surface area (PSA), and refractive index (n) significantly correlated to the biological inhibitory activity of piperazine derivatives. Using QSAR models and in silico pharmacokinetic profiles predictions, five new candidate compounds are selected as potential inhibitors against cancer.
