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.
