Taiwo O. Ojo
Nigeria
Repurposing FDA-Approved Cardiovascular Drugs to Inhibit RAGE in Alzheimers Disease through Virtual Screening and Molecular Dynamics Investigation
Taiwo Ooreoluwa Ojo1*, Temitope Isaac Adelusi1,2, Olawale Quadri Bolaji1,3, Benedicta Quainoo4, Jonathan Cudjoe5, Michael Olanrewaju Faloyo6, Omotoyosi Olanrewaju Osalaye6, Oluwabamise Emmanuel Elegbeleye1, Ibrahim Damilare Boyenle7, Abdul-Quddus Kehinde Oyedele8, Mojeed Ayoola Ashiru4, Abdeen Tunde Ogunlana9
1. Computational Molecular Biology and Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State. Nigeria
2. Department of Surgery, School of Medicine, University of Connecticut Health, Farmington Ave, Farmington, CT 06030, USA
3. National Institute for Pharmaceutical Research and Development, Abuja, Nigeria
4. Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA
5. Department of Chemistry, Kwame Nkruamah University of Science and Technology, Kumasi, Ghana
6. Biomedical Science Department, School of Science, Engineering and Environment, University of Salford, Manchester, United Kingdom
7. Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, USA
8. Department of Chemistry, University of New Haven, West Haven, CT, USA
9. Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
Abstract
Background
Alzheimers disease (AD) is the most prevalent central nervous system (CNS) disorder, marked by the deterioration of brain cells, cognitive decline, and progressive memory loss, leading to deficiencies in language and visuospatial skills. The extracellular plaques of insoluble beta-amyloid (A?) peptide is a notable pathological feature in AD brains. The receptor for advanced glycation end product (RAGE), a multi-ligand protein, is implicated in A?-induced disruptions in cerebral vessels, neurons, and microglia by transporting A? across the blood-brain barrier. Hitherto, efforts to mitigate this menace have been unsuccessful, exemplified by Azeliragon’s failure in the third clinical trial as a RAGE inhibitor in 2018. Thus, there is an urgent need for RAGE VC1 inhibitors where A? binds
Methods
In this research, we attempt to repurpose FDA-approved cardiovascular drugs to inhibit the RAGE VC1 domain and identify compounds that can irreversibly compete with A?. These identified compounds were then evaluated for their ADMET profile and stability through 100ns molecular dynamics simulation. To further expedite their potential, these compounds were screened for their binding-free energy using MM/GBSA calculation.
Results
Following screening of all available FDA-approved cardiovascular drugs, Pravastatin emerged as the best-hit compound and was further optimized at carbon 1 (C-1) to enhance its binding activity. This optimized compound was used to generate random molecules with DataWarrior software. Virtual screening campaign identified three promising drug-like compounds (Compound_67, Compound_183, and Compound_211).
Conclusions
Despite their favorable drug-like and stability properties, further experimental validation is needed to confirm their preclinical relevance for drug development
Leave A Comment