In Silico Pharmacokinetic and Toxicological studies of Novel Trizole Derivatives as Potential Antifungal drug candidates
Keywords:
ADMET Prediction,, Drug- Likeness,, Lipophilicity,, hERG Inhibition,, DILI, Medicinal Chemistry Filters, In Silico PharmacokineticsAbstract
Given the growing problem of invasive mycoses and the emergence of antifungal drug resistance,
new agents with improved in vivo properties and safety are needed. In the past, potent scaffolds
were previously identified by preforming quantitative structure–activity relationship (QSAR) and
docking analysis. Their pharmacokinetic and toxicity properties were evaluated in this study by
ADMET profiling. The selected analogues were comprehensively assessed in silico for their
pharmacokinetic and toxicity characteristics using the SwissADME and ADMETlab 3.0 web
platforms. The water solubility, lipophilicity, physicochemical parameters, and pharmacokinetic
parameters, drug likeliness, medicinal chemistry parameters and toxicity of the compounds were
systematically studied to identify the potential leads for antifungal development. The
investigated compounds were found to have molecular weights ranging from 402.42 to 475.29
g/mol, topological polar surface area (TPSA) ranging from 81.65Ų to 109.89Ų, and consensus
LogP between 2.68 and 4.23, which are good physicochemical properties of orally active
compounds. SwissADME predicted high gastrointestinal absorption for all compounds and none to
traverse the blood–brain barrier. All the compounds met the Lipinski, Ghose, Veber, Egan and
Muegge drug-likeness criteria, had a bioavailability score of 0.55 and were devoid of PAINS and
Brenk structural alerts indicating good medicinal chemistry properties. Analysis of water
solubility showed that compounds 37 and 38 had relatively high-water solubility compared to the
other compounds. The toxicity prediction in ADMETlab 3.0 showed satisfactory safety profiles
with relatively low predicted hERG inhibition and no serious acute toxicity issues. Compounds 33
and 37 were selected as potential antifungal lead compounds based on the comprehensive
evaluation of the pharmacokinetic and medicinal chemistry parameters and toxicity profile.
