Identification of novel SIRT1 activators endowed with cardioprotective profile

Abstract

Drugs targeting epigenetic mechanisms are attracting the attention of scientists since it was observed that the modulation of this post-translational apparatus, could help to identify innovative therapeutic strategies. Among the epigenetic druggable targets, the positive modulation of SIRT1 has also been related to significant cardioprotective effects. Unfortunately, actual SIRT1 activators (natural products and synthetic molecules) suffer from several drawbacks, particularly poor pharmacokinetic profiles. Accordingly, in this article we present the development of an integrated screening platform aimed at identifying novel SIRT1 activators with favorable drug-like features as cardioprotective agents. Encompassing several competencies (in silico, medicinal chemistry, and pharmacology), we describe a multidisciplinary approach for rapidly identifying SIRT1 activators and their preliminary pharmacological characterization. In the first step, we virtually screened an in-house chemical library comprising synthetic molecules inspired by nature, against SIRT1 enzyme. To this end, we combined molecular docking-based approach with the estimation of relative ligand binding energy, using the crystal structure of SIRT1 enzyme in complex with resveratrol. Eleven computational hits were identified, synthesized and tested against the isolated enzyme for validating the in silico strategy. Among the tested molecules, five of them behave as SIRT1 enzyme activators. Due to the superior response in activating the enzyme and its favorable calculated physico-chemical properties, compound 8 was further characterized in ex vivo studies on isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R) period. The pharmacological profile of compound 8, suggests that this molecule represents a prototypic SIRT1 activator with satisfactory drug-like profile, paving the way for developing novel epigenetic cardioprotective agents.