Therapeutic strategy to identify potential RAGE inhibitors against Alzheimer’s disease: An in-silico approach

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder caused by the accumulation of senile plaques composed of amyloid beta (Aβ) protein and neurofibrillary tangles of abnormal hyperphosphorylated tau (τ) protein. The receptor for advanced glycation end products (RAGE) is the immunoglobulin superfamily receptor that can bind to numerous extracellular and intracellular ligands leading to inflammatory disorders including cancer, diabetes, and Alzheimer’s disease (AD). This study aims to identify the potential RAGE inhibitors through in-silico molecular modeling approaches. Here we performed structure-based virtual screening of 556,773 compounds from various databases to identify prospective lead compounds. The resultant molecules with good glide scores were assessed via molecular docking studies to check their inhibitory effect against RAGE (PDB: 6XQ3). The top five hits with a binding affinity (<-6.0 kcal/mol) were further subjected to molecular dynamic (MD) simulations for 100ns to identify the stability of the hit compounds with RAGE. Furthermore, the top five hits were selected for the binding free energy calculation through Prime/MM-GBSA, perresidue decomposition analysis, and ADMET evaluation. These results indicate that the hit compounds IBSNC and IBSSC3 can be used for further in-vitro analysis and could be a promising candidate for targeting RAGE protein and acting as an anti-Alzheimer drug.