In silico rationalization of piperidin-4-one analogs as anaplastic lymphoma kinase inhibitors: Integration of density functional theory, topological descriptor, molecular docking and pharmacological feature profiling

Abstract

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we designed a novel ALK inhibitor Piperidin-4-One based on the structure of the second-generation ALK inhibitor ceritinib. The target compound 1-(cyclopropanecarbonyl)-2,6-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-methylpiperidin-4-one (CDMP) was computed using density functional theory (DFT) method. The stability and charge delocalization of the molecule was also studied by natural bond orbital (NBO) analysis. The HOMO-LUMO energies describe the charge transfer takes place within the molecule. Molecular electrostatic potential has been analyzed. The reported molecule used as a potential NLO material since it has high µβ0 value. Additionally, statistical analyses were conducted to clarify the connections between ADMET properties of CDMP and molecular descriptors based on degree, neighborhood degree, degree entropy and neighborhood degree entropy. This thorough examination seeks to uncover the complex interactions between Density Functional Theory and molecular descriptors, offering valuable insights into the relationships among CDMP drug properties. The binding mode mechanism of the title compound was investigated through molecular docking studies, focusing on cancer-related proteins such as 4TT7, 5FTO and 3AOX. Furthermore, an assessment of Drug-likeness and ADMET properties revealed favorable pharmacokinetic profiles for the compound, with no indications of toxicity observed.