<i>In silico</i> studies of triazole derivatives as inhibitors for estrogen receptor (ER) mutant L536S and anaplastic lymphoma kinase: DFT/tD-DFT, molecular docking, and MD simulations

From the most prevalent cancers, breast and lung cancers have a meager survival rate for both men and women. These two cancers are related to each other. Breast cancer can possibly spread to the lungs or the region between the lung and the chest wall. The organic heterocyclic compounds are expected to possess some anti-cancerous properties. Hence, this study is to investigate the molecular characteristics of the derivatives of alkyl-5-hydroxy-7-aryl-5-methyl-1,3-dioxo-2-phenyl hexahydropyrazolo[1,2<i>a</i>] (Asif, 2017; Hei et al., 1996; Kumar et al., 2013) triazole-6-carboxylate and the drugability of these compounds have also been examined against estrogen receptor (ER) mutant L536S, which causes ER-positive breast cancer, and anaplastic lymphoma kinase responsible for non-small cell lung cancer (NSCLC). DFT and TDDFT have been used to study all the derivatives with B3LYP/6-311++G(d, p) basis set. Substituent effects <i>via</i> ¹H NMR,¹³C NMR, IR, UV and HOMO-LUMO energy gaps of -CH₃, -F, -Cl, -Br, -I, -NO₂, and -SO₃H groups at the para positions of 7-aryl substituent present in triazole compound have been studied. The global reactivity of these compounds is also being discussed in terms of band gap (E_HOMO-E_LUMO). The NTO analysis monitors and characterizes the direction and nature of charge transfer. The drug-likeness using Lipinski's Rule of Five, followed by molecular docking of the compounds with the target proteins have also been studied. Molecular dynamics simulations and free energy calculations were conducted for all protein-ligand complexes to predict potential inhibitors targeting the proteins.