Rational drug repurposing for alzheimer’s treatment using in-silico ligand and structure-based approaches

Karishma  Rathi; Ravindra  Wavhale; Ritesh  Bhole; Vaishali  Undale; Somdatta  Chaudhari

doi:10.1590/

Authors

Karishma Rathi Department of Pharmacy Practice & Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India https://orcid.org/0000-0002-6407-6739
Ravindra Wavhale Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India
Ritesh Bhole Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India; Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
Vaishali Undale Department of Pharmacy Practice & Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India
Somdatta Chaudhari Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Nigdi, India

DOI:

https://doi.org/10.1590/

Keywords:

Alzheimer’s disease, Structure-based screening, Swiss similarity, Ligand-based screening, FDA approved drugs, Docking

Abstract

Alzheimer’s disease is a devastating neurodegenerative disorder characterized by memory loss and cognitive decline. New AD treatments are essential, and drug repositioning is a promising approach. In this study, we combined ligand-based and structure-based approaches to identify potential candidates among FDA-approved drugs for AD treatment. We used the human acetylcholinesterase receptor structure (PDB ID: 4EY7) and applied Rapid Overlay of Chemical Structures and Swiss Similarity for ligand-based screening.Computational shape-based screening revealed 20 out of 760 FDA approved drugs with promising structural similarity to Donepezil, an AD treatment AChE inhibitor and query molecule. The screened hits were further analyzed using docking analysis with Autodock Vina and Schrodinger glide. Predicted binding affinities of hits to AChE receptor guided prioritization of potential drug candidates. Doxazosin, Oxypertine, Cyclopenthiazide, Mestranol, and Terazosin exhibited favorable properties in shape similarity, docking energy, and molecular dynamics stability.Molecular dynamics simulations confirmed the stability of the complexes over 100 ns. Binding free energy analysis using MM-GBSA indicated favourable binding energies for the selected drugs. ADME, formulation studies offered insights into therapeutic applications and predicted toxicity.This comprehensive computational approach identified potential FDA-approved drugs (especially Doxazosin) as candidates for repurposing in AD treatment, warranting further investigation and clinical assessment.

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