Abstract
Nonprenylated rotenoids isolated from Boerhaavia diffusa are identified as new class of breast cancer resistance protein inhibitors (ABCG2). The recent determination of high-resolution structure of ABCG2 (with chemotherapeutics mitoxantrone or Ko143) enables the investigation of molecular interaction capacities of boeravinones. In this research pharmacokinetic/pharmacodynamic relationship of 17 boeravinones considering their molecular properties, ADMET profile and binding energies for ABCG2 was studied for the first time. All 17 compounds met the requirements of empirical rules for drug-likeness. Based on the obtained results lipophilicity was determined as the key property of boeravinones for the intestinal absorption, total clearance and acute and chronic toxicity in rats while polarity was the limiting factor for blood brain barrier permeation. Both lipophilicity and the fraction of sp3 hybridized carbon atoms influenced the binding affinity of boeravinones to ABCG2 proteins (6XVI and 6FFC) expressed as ChemPLP and GOLD Score. The performed in silico analysis implies that boeravinones could be used as potent safe leads to human ABCG2.
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