QUANTITATIVE STRUCTUREâ€“PHARMACOKINETICS RELATIONSHIP FOR PLASMA PROTEIN BINDING OF NEUTRAL DRUGS
Keywords:Plasma protein binding (PPB), Nil, In silico prediction, Human serum albumin (HSA), Alpha-1-acid glycoprotein (AGP)
Objective: Plasma protein binding (PPB) of drugs is important pharmacokinetic (PK) phenomena controlling the free drug concentration in plasma and the overall PK and pharmacodynamic profile. Prediction of PPB at the very early stages of drug development process is of paramount importance for the success of new drug candidates. The study presents a quantitative structureâ€“pharmacokinetics relationship (QSPkR) modelling of PPB for neutral drugs.
Methods: The dataset consists of 117 compounds, described by 138 molecular descriptors. Genetic algorithm and stepwise multiple linear regression are used for variable selection and QSPkR models development. The QSPkRs are evaluated by internal and external validation procedures.
Results: A robust, significant and predictive QSPkR with explained variance r2 0.768, cross-validated q2LOO-CV 0.731,and geometric mean fold error of prediction (GMFEP) 1.79 is generated, which is able to predict the extent of PPB for 67.6% of the drugs in the dataset within the 2-fold error of experimental values. A simple empiric rule is proposed for distinguishing between drugs with different binding affinity, which allowed correct classification of 78% of the high binders and 87.5% of the low binders.
Conclusions: PPB of neutral drugs is favored by lipophilicity, dipole moment, the presence of substituted aromatic and fused rings and a nine-member ring system, and is disfavored by the presence of aromatic N-atoms.
Keywords: Plasma protein binding (PPB), Quantitative structureâ€“pharmacokinetics relationship (QSPkR), In silico prediction, Human serum albumin (HSA), Alpha-1-acid glycoprotein (AGP).
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