3.1.3. Global and Local Reactivity Descriptors

The HOMO and LUMO frontier orbitals are used to predict chemical reactivity. The HOMO orbital energy of a compound is significantly correlated with its vulnerability to electrophilic attack and ionization potential. A compound's LUMO orbital energy is a reliable predictor of electron affinity and nucleophilic attack. The energy of LUMO is proportional to its electron affinity, indicating that it is susceptible to nucleophile attack. The frontier molecular orbital energies are also related to the hard and soft characteristics of a molecule. Hard nucleophiles have a low HOMO, whereas soft nucleophiles have a high HOMO. Similarly, hard electrophiles have a high LUMO energy, whereas soft electrophiles have a low LUMO energy. According to the frontier theory of electron reactivity, the chemical reaction occurs at the point where the HOMO and LUMO have the most overlap. All reactions require the HOMO density of the donor molecule, while all reactions require the LUMO density of the acceptor molecule. The frontier orbital densities of individual atoms can be used to quantify their reactivity inside a molecule. Chemical behavior is frequently predicted using electronegativity and hardness. Compound **248** presented greater energy gaps, indicating it to be the tougher among all compounds. Compound **208** demonstrated the greatest electrophilicity index value of 0.207 eV. This indicates that compound **208** is an excellent electrophile among all the other compounds. The HOMO– LUMO energy gap for Dabrafenib was found to be 0.159 eV. Dabrafenib showed a softness value of 6 (Table 3). The Koopman's theorem was used to express ionization energy and electron affinity of drug candidates.

$$\text{I} = -\text{EHOMO:}\,\text{A} = -\text{ELUMO}$$


**Table 3.** Global reactivity descriptors.

We evaluated the following parameters by using their respective formulas: Hardness: η = 1/2(ELUMO − EHOMO); Softness: S = 1/2η; Electronegativity: χ = −1/2(ELUMO + EHOMO); Chemical potential: µ = −χ; Electrophilicity index: ω = µ/2η.
