Structure-Based Design of Hybrid Molecules Exhibiting Dual SGLT2 and AT1 Inhibition for Cardiorenal Protection: A Computational and Medicinal Chemistry Strategy

Combination therapy for metabolic diseases has traditionally been associated with an increased risk of chronic kidney disease (CKD). However, the co-administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin II type I receptor antagonist (AT1) have demonstrated a protective effect against CKD progression. To build upon this therapeutic potential, the present study introduces an in silico design of a hybrid molecule as an innovative pharmacological strategy.

This approach integrates the key pharmacophores of empagliflozin (SGLT2 inhibitor) and telmisartan (ARB) into a single molecular entity, aiming to enhance nephroprotective synergy while streamlining the treatment regimen. The computational workflow began with the generation of a bioisostere library comprising 2017 compounds sourced from the Zinc20 database. Molecular docking simulations were conducted using the VINA 1.1.2 algorithm to assess binding affinity and stability toward both target receptors: SGLT2 (PDB: 7VSI) and AT1 (PDB: 4ZUD).

The lead candidate was identified based on its optimal Gibbs free energy values for both receptors and its favorable pharmacokinetic and safety profile, as predicted by ADMETlab 3.0. Visualization and analysis of docking interactions were performed using PyMOL and Discovery Studio.

This study not only confirms the feasibility of combining two complementary mechanisms of action within a single compound but also proposes a promising candidate for subsequent development stages, including chemical synthesis and preclinical evaluation (in vitro and in vivo). These findings lay the groundwork for a new generation of targeted therapies that are safer and more effective in protecting kidney and cardiovascular health.