3.1.2. Frontier Molecular Orbital (FMOs)

The way a molecule interacts with other species is determined by its frontier molecular orbitals. The highest occupied molecular orbital, or HOMO, is the outermost orbital-bearing electrons, and it primarily works as an electron donor. The lowest unoccupied molecular orbital, or LUMO, is the innermost orbital with free electron acceptor sites. The ionization potential ought to be proportional to the HOMO energy, while the LUMO energy should be proportional to the electron affinity (Table 2).


**Table 2.** ∆Egap of HOMO/LUMO orbitals of selected compounds.

The energy gap is the difference in energy between the HOMO and LUMO orbitals, and it is the most key variable in predicting the stability of a molecule. The HOMO–LUMO energy gap is used to evaluate the chemical reactivity and kinetic stability of the molecule. A soft molecule is a structure with a narrow gap that has a higher degree of polarization. As a measure of electron conductivity, the energy difference between HOMO and LUMO was recently employed to illustrate the bioactivity of intramolecular charge transfer (ICT). The stronger the chemical reactivity and the less stable the kinetics, the smaller the gap. The compound **762** has the narrowest energy gap at 0.127 eV among all the compounds. Compound **248** has a greater energy gap, measuring 0.152 eV. Thus, it shows compound **762** is chemically more reactive than all other compounds, which are comparatively the stable ones. In addition, the electron density of HOMO orbitals for Dabrafenib was localized over morpholine and piperdinyl rings, whereas electron density of LUMO is localized to the carbonitrile and benzocarbazole moiety of the drug. FMOs orbitals are shown in Figure 4.

**Figure 4.** HOMO–LUMO structures of the selected compounds.
