Computational pharmacology and computational chemistry of 4-hydroxyisoleucine: Physicochemical, pharmacokinetic, and DFT-based approaches

Computational pharmacology and chemistry of drug-like properties along with pharmacokinetic studies have made it more amenable to decide or predict a potential drug candidate. 4-Hydroxyisoleucine is a pharmacologically active natural product with prominent antidiabetic properties. In this study, ADMETLab 2.0 was used to determine its important drug-related properties. 4-Hydroxyisoleucine is compliant with important drug-like physicochemical properties and pharma giants’ drug-ability rules like Lipinski’s, Pfizer, and GlaxoSmithKline (GSK) rules. Pharmacokinetically, it has been predicted to have satisfactory cell permeability. Blood–brain barrier permeation may add central nervous system (CNS) effects, while a very slight probability of being CYP2C9 substrate exists. None of the well-known toxicities were predicted in silico, being congruent with wet lab results, except for a “very slight risk” for respiratory toxicity predicted. The molecule is non ecotoxic as analyzed with common indicators such as bioconcentration and LC(50) for fathead minnow and daphnia magna. The toxicity parameters identified 4-hydroxyisoleucine as non-toxic to androgen receptors, PPAR-γ, mitochondrial membrane receptor, heat shock element, and p53. However, out of seven parameters, not even a single toxicophore was found. The density functional theory (DFT) study provided support to the findings obtained from drug-like property predictions. Hence, it is a very logical approach to proceed further with a detailed pharmacokinetics and drug development process for 4-hydroxyisoleucine.