Design and optimisation of novel Histone Deacetylase (HDAC) inhibitors based on the AR-42 scaffold

Abstract

Cachexia is characterized by the decline of both skeletal and visceral muscle mass (Gordon et al., 2005). This condition is a comorbidity of chronic conditions and its occurrence is associated with a worsened prognosis and quality of life [Honda et al, 1995; Vanghan et al, 2013]. Tseng et al demonstrated that the novel histone deacetylase inhibitor Ar-42 mitigated cancer induced cachexia, such property was not noted with other histone deacetylase inhibitors. To utilize a dual modal approach to develop two different molecular cohorts with the aim of mimicking AR-42 anti cachexic properties. The dual modal approach used consisted of a virtual screening and a de novo approach, for the virtual screening approach, the consensus pharmacophore was modeled using the critical contacts of both the optimal Ar-42 conformer and vorinostat. The consensus pharmacophore was submitted to Zinc Pharmer® (Koes & Camacho, 2012). Where virtual screening was carried out, the obtained molecular cohort was filtered and scored according to affinity. For the de novo approach, novel molecules were obtained from fragmented seed structures which were computationally linked together. The 65 Lipinski rule compliant molecules, which were identified from the virtual screening approach, were scored according to their affinity to the target protein. The highest total score was 7.5908, while the lowest total score was 2.7962. The de novo approach resulted in 331 novel molecules which were obtained from 4 different seeds. The highest ranked molecules from both cohorts were compared to each other. Ideally the novel molecules obtained from both approaches mimics AR-42 anti-cachexic properties.