Druggable targets to contrast Alzheimer's disease: molecular modelling approaches for the drug design process

Alzheimer’s disease (AD) is a neurodegenerative disorder with epidemic proportions, being declared a “global public health priority” by World Health Organization (WHO). Traditional strategies such as targeting acetylcholinesterase (AChE) and N-methyl-D-aspartate receptors (NMDAr) only led to the development of symptomatic treatments with limited efficacy over time. However, several other targets were individuated as druggable macromolecules for AD. Among them, we selected the trace amine-associated receptor 1 (TAAR1), lanthionine synthetase C-like protein-2 (LANCL2) and Sirtuin-2 (SIRT2). Such targets are associated to at least one experimental structure, allowing a structure-based approach in the search of new modulators. The research project employs computational techniques with the final aim to design novel compounds with neurodegeneration-related therapeutic potential. The SIRT2 project involved a structure-based virtual screening (SBVS) campaign, leading to the discovery of novel chemo-types endowed with modest SIRT2 inhibitory activity. Further studies on the target led to individuate novel pyrazolo-pyrimidines and thiazole-based compounds exhibiting ameliorated SIRT2 inhibitory activity. As regards the discovery of LANCL2 agonists, the protein LANCL2 was submitted to a computational study including molecular docking and long molecular dynamic (MD) simulations. In particular, the enzyme in complex with two LANCL2 agonists, abscisic acid (ABA) and BT-11, has been evaluated. The derived pharmacophore model was used for the discovery of a novel LANCL2 agonist (AR-42). A few TAAR1 agonists were recently discovered in a medicinal chemistry effort and computational methods by our group. Such compounds were submitted to extensive docking in the thirteen cryo-electron microscopy (Cryo-EM) structures of TAAR1 followed by clustering and MD simulations. A binding mode of the compounds was proposed, leading to the suggestion of new (potentially) optimized compounds.