In Silico Predictions for Improving Permeability Properties of Principal Anticancer Anthracyclines through Structural Modification

摘要

A method, probably the best one, to improve anticancer drugs permeability isstructural modification on the base of drug-likeness fundamental concepts in the way of reducingionizability and polarity, reducing number of hydrogen bond donors or acceptors and increasinglipophilicity. The present work looks forward to modify structure of major anticancer anthracyclines inorder to improve their permeability, with a final aim to increase absorption and oral bioavailability.SmiLib v2.0 was used first to build a combinatorial library, by virtual reactions of building blocks(from antimetabolite and/or antineoplastic drugs) with scaffold molecules (the tetracene-5,12-dionemoiety of anthracyclines). Second, ADME-Tox web-based software tool (hosted on the server of theRessource Parisienne en Bioinformatique Structurale) was used to mass-computation of the mostrelevant physicochemical properties for drug-likeness and oral bioavailability for all anthracyclinevirtual derivates from combinatorial library. Qualified derivates as potential drugs were tested forgenotoxicity and acute toxicity with Tox Boxes version 2.0. Sixteen from 160 derivates created withSmiLib v2.0 were qualified as drug-like compounds with good oral bioavailability. In silico toxicitytests showed that all derivates have good values for oral administration. One derivate presented asmaller genotoxicity and much better values for acute toxicity at oral, subcutaneous and intraperitonealadministration than any of anthracyclines. Only at intravenous administration this derivate showedcertain acute toxicity, but the aim of the study was to improve the oral bioavailability.