Theoretical Drug-likeness, Pharmacokinetic and Toxicities of Phytotoxic Terpenoids from the Toxic Plants-Phytotoxins
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Abstract
Pharmacokinetic and toxicity-related properties are the major causes of attrition in drug development. The emerging roles of terpenes in drug discovery require an understanding of these properties for structure modification and possible repurposing. This study evaluated the drug-likeness, pharmacokinetic, and toxicity profiles of diverse phytotoxic terpenes obtained from the Toxic Plants–Phytotoxins (TPPT) database using different in silico algorithms. The database, of 1586 phytotoxins, was filtered to obtain 576 phytotoxic terpenoids (PhytoTerp). The Lipinski parameters, potential targets, pharmacokinetic profiles and toxicity on various organ endpoints were implemented using SwissADME, SwissTargetPrediction, the pkCSM and ProTox II webservers. Drug likeness prediction showed that 9.55% of the PhytoTerp obeyed Lipinski’s rule of five. The toxicity profiles showed that none of the compounds inhibited hERG I, while 12.73% inhibited hERG II. In addition, 25.45% of the compounds elicited both AMES and liver toxicities; and 32.73% caused skin sensitivity. Furthermore, 72.73 and 76.36% showed high Caco-2 and skin permeability respectively. The p-glycoprotein was extruded by 29.09% and inhibited by 34.45% of PhytoTerp; 47.27% of the compounds readily crossed the blood-brain barrier, 23.64% penetrated the central nervous system, 56.36% were sensitive to cytochrome p450 isoenzymes, 36.37% inhibited cytochrome p450 isoenzymes, 49.09% were immune-toxic, 1.82% were toxic to cells, 14.55% would cause cancer, and 21.82% showed high tolerated doses in humans. All the PhytoTerp demonstrated high intestinal absorption while a significant number demonstrated moderate bioavailability. This study identified marrubiin and nine other terpenoids as drug-like, non-toxic, and highly bioavailable with potential for further optimization, and development.
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