Abstract
The combined use of in vitro (19F-NMR) and in silico (molecular docking) procedures demonstrates the affinity of a number of human calycins (lipid-binding proteins from ileum, liver, heart, adipose tissue and epidermis, and retinol-binding protein from intestine) for different drugs (mainly steroids and vastatins). Comparative evaluations on the complexes outline some of the features relevant for interaction (non-polar character of the drugs; amino acids and water molecules in the protein calyx most often involved in binding). Dissociation constants (Ki) for drugs typically lie in the same range as Ki for natural ligands; in most instances (different proteins and docking conditions), vastatins are the strongest interactors, with atorvastatin ranking top in half of the cases. The affinity of some calycins for some of the vastatins is in the order of magnitude of the drug Cmax after systemic administration in humans. The possible biological implications of this feature are discussed in connection with drug delivery parameters (route of administration, binding to carrier proteins, distribution to, and accumulation in, human tissues).
Highlights
Carrier proteins in plasma are able to bind a number of exogenous compounds—including drugs—with close to distant resemblance to the endogenous ligands [1, 2]. This interaction, which mainly involves albumin [3] and α1-acid glycoprotein/orosomucoid [4], features low selectivity but high capacity, and greatly impacts on the pharmacokinetic and pharmacodynamic profile of the therapeutic agents
Extensive literature data support the notion that calycins are able to bind a variety of both natural and synthetic compounds
Among the latter, during focused investigations, interaction has been demonstrated between selected calycins and selected drugs
Summary
Carrier proteins in plasma are able to bind a number of exogenous compounds—including drugs—with close to distant resemblance to the endogenous ligands [1, 2]. This interaction, which mainly involves albumin [3] and α1-acid glycoprotein/orosomucoid [4], features low selectivity but high capacity (large amounts of heterogeneous substances being bound by these abundant plasma proteins), and greatly impacts on the pharmacokinetic and pharmacodynamic profile of the therapeutic agents. Plasma protein level variations with age (with the extreme case of the rapidly changing concentrations in newborns) [5] and between sexes [6, 7] do influence drug distribution. Differences in the binding sites across species [9, 10] are confounding factors in translational medicine
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