Multilayered screening for multi-targeted anti-Alzheimer's and anti-Parkinson's agents through structure-based pharmacophore modelling, MCDM, docking, molecular dynamics and DFT: a case study of HDAC4 inhibitors.

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurological conditions that primarily impact the elderly having distinctive traits and some similarities in terms of symptoms and progression. The multifactorial nature of AD and PD encourages exploring potentiality of multi-target therapy for addressing these conditions to conventional, the "one drug one target" strategy. This study highlights the searching of potential HDAC4 inhibitors through multiple screening approaches. In this context, structure-based pharmacophore model, ligand profiler mapping and MCDM approaches were performed for target prioritization. Similarly, ligand profiler, MCDM and Docking studies were performed to prioritize multi-targeted HDAC4 inhibitors. These comprehensive approaches unveiled 5 common targets and 5 multi-targeted prioritized compounds consensually. MD simulations, DFT and binding free energy calculations corroborated the stability and robustness of propitious compound 774 across 5 prioritized targets. In conclusion, the screened compound 774 (ChEMBL 4063938) could be a promising multi-targeted therapy for managing AD and PD further rendering experimental validation. Graphical abstract: Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00302-4.