In silico methods for predicting physico-chemical properties and biological activity of newly synthesized esters of Bexarotene

Abstract

The synthetic retinoid analogue Bexarotene (Targretin®, Ligand Pharmaceuticals Inc.) belongs to a group of compounds called rexinoids. They possess a specific affinity for the retinoid X receptor. The latter plays a role in the regulation of cell growth and differentiation through their ability to regulate transcription. Bexarotene is approved for the treatment of cutaneous T-cell lymphoma (CTCL), both as an oral and dermal dosage form. A total of 4 new Bexarotene esters were synthesized and an in silico analysis was performed using the OECD QSAR Toolbox, Molinspiration, PreADME/Tox and SwissADME software. The QSAR Toolbox results show that Bexarotene esters possess high metabolic activity with metabolites similar to those of Bexarotene. Alsom a hydrolysis process is observed making the esters act as prodrugs. According to Lipinski’s rule of 5 all four Bexarotene derivatives give 1 violation and therefore have drug-like properties. The Molinspiration and SwissADME software showed affinity of the newly synthesized molecules for nuclear receptors which partly rejects the prodrug theory. After evaluating the pharmacokinetic profile of the esters, it was observed that the molecules present promising intestinal absorption, distribution, metabolism, excretion and toxicity (ADME/T) characteristics. Even though the in silico analysis gave promising results, further investigation is needed.