## 2 Results
### Physiochemical Properties Impacting ADMET
However, their inability to cross the blood\(-\)brain barrier (BBB) limits their direct therapeutic application for central nervous system (CNS) disorders. Despite this limitation, the high GI absorption of apigenin suggests its potential for addressing systemic oxidative stress and inflammation, particularly in peripheral tissues [36]. Furthermore, apigenin's non-substrate status for permeability glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, reduces the likelihood of active efflux, enhancing its bioavailability in peripheral circulation. The lack of BBB permeability may also have positive implications in reducing off-target effects in the CNS, minimizing risks of neurotoxicity while concentrating therapeutic action in non-CNS tissues. This characteristic makes apigenin particularly promising for conditions like Long COVID-19, where oxidative stress and inflammation are predominant in peripheral tissues rather than the CNS [31]. Additionally, apigenin's pharmacokinetics should be further optimized to address its relatively low bioavailability due to rapid metabolism and clearance. Formulation strategies, such as nanoencapsulation, co-crystallization, or prodrug development, could enhance its stability and systemic availability. Moreover, while the pharmacokinetic profile of apigenin poses certain challenges, its high GI absorption and favorable interaction with P-gp offer significant therapeutic potential for systemic applications, particularly in conditions driven by oxidative stress and inflammation outside the CNS [37]. Drug-likeness assesses the likelihood of a chemical becoming an oral drug in terms of bioavailability. This assessment is based on structural or physicochemical evaluations of compounds that have progressed to be considered potential oral drug candidates [38]. The concept of drug-likeness is commonly used to screen chemical libraries to exclude compounds with characteristics likely incompatible with a favorable pharmacokinetic profile [39]. Ligand has positive Lipinski values without any violations and has a negative Ghose value with three violations (MW \(<\) 160, MR \(<\) 40, #atoms \(<\) 20). Additionally, apigenin has positive Veber and Egan values. Interestingly, selected ligand has the same bioavailability score of 0.55 each. The Medicinal Chemistry section aims to support medicinal chemistry's routine drug development [40]. Despite the absence of alerts for PAINS assessment, apigenin is not associated with any PAINS alerts. Apigenin positively influences lead-likeness, a key factor in computer-aided drug design (CADD). This process focuses on selecting the most promising molecules for synthesis and further biological or other investigations. Synthetic accessibility (SA) is a critical component of this evaluation, apigenin has an SA value of 2.96, indicating its potential for practical synthesis [41]. The AMES toxicity test is a widely utilized method for assessing a substance's mutagenic potential using bacteria. A positive result indicates mutagenicity, suggesting a potential risk of carcinogenesis. Apigenin exhibits no mutagenic potential. The Maximum Recommended Therapeutic Dose (MRTD) estimates a chemical's hazardous dosage threshold in humans [42]. Apigenin has the lowest MRTD values at 0.328, indicating its high safety profile. Remarkably, apigenin does not demonstrate hepatotoxicity, skin sensitization, or inhibitory effects on hERG I and II channels. Assessing a compound's potential hazards is crucial, and lethal dose estimates (LD50) are used to evaluate the acute toxicity of various compounds. The LD50 represents the dose at which 50% of test animals succumb to the compound when administered simultaneously. Apigenin exhibits the lowest LD50 values at 2.45 mol/kg, reflecting its low acute toxicity. Additionally, apigenin has a lower LOAEL value, further supporting its favorable safety profile.