Virtual Screening for Dual Inhibitors of HDAC6 and MPO: A Multistep Approach Integrating Chemical Space Analysis and Molecular Docking

Abstract Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for ∼17.9 million deaths annually. Despite therapeutic advances, treatments face limitations, such as adverse effects, drug resistance, and high costs. CVDs involve complex biological networks and compensatory pathways that limit the efficacy of single-targeted therapies. In this context, the multitarget-directed ligand (MTDL) strategy has emerged as a promising approach to enhance therapeutic efficacy by modulating proteins in different biochemical pathways involved in disease progression. Thus, this work reports a virtual screening study aimed at identifying novel dual inhibitors targeting histone deacetylase 6 (HDAC6) and myeloperoxidase (MPO), two enzymes implicated in the pathophysiology of CVDs and associated risk factors, for which no multitarget inhibition studies have been reported to date. Both targets converge in exacerbating CVDs by driving vascular inflammation and impairing cardiac autophagy. In this way, a ligand- and structure-based virtual screening approach was employed to identify potential multitarget hit compounds. The selection of reference compounds for virtual screening was based on four strategies combining the lowest IC50 values, clinical status, and shared physicochemical properties between the inhibitors of both enzymes, selected from a chemical space analysis. Molecular similarity was assessed via the Tanimoto index using reference ligands followed by molecular docking. Molecules 11 and 16 emerged as putative dual inhibitors, exhibiting structural similarity and crucial active-site interactions with HDAC6 (Zn2+) and MPO (heme, His95, Arg239). These findings support further investigation of these molecules as potential lead compounds for a dual-target cardiovascular therapy.