Computational Insights into an Antifolate Drug, Talotrexin: A Multi‐Scale Approach using DFT, Docking, and Molecular Dynamics Simulations

Abstract The present investigation performed Density Functional Theory (DFT)‐based quantum chemical analysis on Talotrexin, an antifolate drug. Critical descriptors of reactivity (e.g., local and global reactivity parameters, the HOMO‐LUMO energy gap) were calculated. The drug's HOMO and LUMO orbitals are delocalized over the entire chemical structure, making it stable. The chemical stability was confirmed by the high value of ionization potential along with the low value of electron affinity. The compound displayed negative chemical potential, thereby classifying it as a chemical donor. Biological activities were predicted using maps of molecular electrostatic potential contour. Further, natural bond orbital (NBO), non‐covalent interactions (NCI), electron localization function (ELF) and localized orbital locator (LOL) provided understandings into the charge delocalization and its chemical nature. Furthermore, the molecular docking score of the Talotrexin‐TNF alpha interaction was calculated as −8.5 kcal mol −1 , which relates to a binding affinity of 1.72 × 106 M −1 , with non‐covalent interactions providing stability to the complex. Stability of the complex was also confirmed with molecular dynamics simulations for 100 ns. This bioinformatics analysis not only illuminates its possible chemical interactions but also paves the way for studies of its reactivity in different contexts, aiding the design of new drugs of higher value.