Computational Study on the Reactivity and Inhibition of Arginine Gingipain B, a Potential Target for the Treatment of Alzheimer's Disease

Abstract

Since its identification in 1901, by the German psychiatrist Alois Alzheimer, Alzheimer's disease has emerged as one of the greatest challenges in pharmaceutical research. In 2019, the cysteine protease RgpB was identified as a possible new pharmacological target for the development of neuroprotective treatments using small drugs-like molecules. This thesis represents an effort to shed light on atomic-level details of the mechanisms by which the RgpB works and the processes of its inhibition by small-molecule drug candidates. For this purpose, a comprehensive computational study combining methods based on classical molecular dynamics and hybrid quantum mechanics/molecular mechanics molecular dynamics was carried out. These methods were employed to obtain reaction free energies and binding free energies. This allows us to elucidate the mechanism by which the proteolysis reaction proceeds on RgpB, to characterize non-covalent interaction profiles between putative inhibitors and RgpB and to unravel the covalent binding mechanisms of such irreversible inhibitors.