https://doi.org/10.1140/epjp/s13360-024-05732-9
Regular Article
Computational bioisosteric investigation of sulindac derivatives for targeted inhibition in Alzheimer’s disease: DFT, molecular docking, and ADME/T profiling
1
Department of Physics, National Institute of Technology Durgapur, Durgapur, India
2
Department of Physics, The Bhawanipur Education Society College, Kolkata, India
Received:
28
August
2024
Accepted:
9
October
2024
Published online:
7
November
2024
Alzheimer’s disease (AD) is characterized by the formation of amyloid plaques and neurofibrillary tangles, resulting in neurodegenerative symptoms in the elderly. Amyloid beta and its precursor proteins along with their several mutations cause early-onset AD. Though, a well-known nonsteroidal anti-inflammatory drug, Sulindac has been found to block the A
42 peptide’s production in cultured cells, it has a questionable blood–brain barrier (BBB) permeability, which is necessary for AD-inhibiting drugs. In this paper, we use computational bioisosteric replacement of Sulindac to detect the derivatives with better pharmacokinetics and lead activity. Replacing important fragments of the parent molecule, structural modifications of Sulindac have been done with the aim of finding prospective drug candidates using consecutive screenings with quantum mechanical DFT calculations and protein–ligand docking. Finally, we shortlist 12 new drug candidates out of the huge spectrum of probable bioisosters, based on optimal stability, better docking energy, and desired ADME/T properties, highlighting BBB permeability. All these 12 derivatives, when computationally probed, have shown better BBB permeability as well as increased activity in A42 inhibition and reduction of neuroinflammation.
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© The Author(s), under exclusive licence to Società Italiana di Fisica and Springer-Verlag GmbH Germany, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
