In silico investigations of triazole -trimethoxyphenyl hybrids as anti-proliferative agents against adenocarcinomic human alveolar basal epithelial cells (A549): DFT, QSAR and Molecular Docking Approaches

Abstract

Abstract Twenty-eight sets of synthesized triazole-trimethoxyphenyl hybrids (TPD) were considered as anti-proliferative drugs against human alveolar basal epithelial (A549) cancer cell lines using DFT, QSAR, ADMET profile and molecular docking methods. The considered compounds were used to develop a robust QSAR model, which was used to design new triazole-trimethoxyphenyl compounds that could serve as anti-proliferative drug candidate against human alveolar basal epithelial (A549) cancer. The parameters obtained from DFT calculations such as the HOMO, LUMO, Dipole moment, chemical hardness and softness favoured TPD-11 and TPD-25 over etopoxide as strong inhibitors against human alveolar basal epithelialcancer cell (A549), which agreed with the experimental data. The QSAR modeling and validation indicated the major influence of MATS4p, minHBint3, and ATSC7c descriptors on the reported anticancer activity of the drugs in the A549- MLR-GFA QSAR (R2 = 0.8632, adjusted R2 = 0.7951, Q2Loo = 0.6023 and R2 - Q2Loo = 0.2609). By leveraging data from the model, four new triazole-trimethoxyphenyl hybrids were proposed (NTPD-3, NTPD-4, NTPD-6 and NTPD-9). The DFT and molecular docking analysis showed these four compounds could be good inhibitors against adenocarcinomic human alveolar basal epithelial cells (A549) than etopoxide. However, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties revealed NTPD-6 showed excellent pharmacokinetic and toxicological profiles and might serve as a road map for new and more effective anticancer agents.