Computational investigation of BMS-984923 against Alzheimer's amyloid-beta (Aβ) structures: insights into their molecular interactions and inhibition of aggregation.

Normal brain function involves soluble Aβ peptides that support synaptic activity. However, Aβ peptides are prone to aggregation under abnormal or pathogenic conditions, forming clumps known as oligomers and protofibrils, which subsequently lead to the formation of mature, stable β-sheet rich fibrils. The accumulation of such misfolded amyloid aggregates in the brain is the hallmark of Alzheimer's disease (AD). Recent experimental studies suggested that BMS-984923 successfully blocks the action of Aβ induced toxicity while preserving glutamate signaling via the metabotropic glutamate receptor 5 (mGluR5), which is a key excitatory neurotransmitter in the brain. However, the molecular mechanism by which BMS-984923 interacts with Aβ peptide remains unclear. In this work, we investigated the inhibitory mechanism of BMS-984923 against the Aβ monomeric structures with the help of molecular docking and molecular dynamics (MD) simulations. To elucidate the atomic level interactions, we employed DSSP for performing secondary structure analysis, MM-PBSA, per-residue decomposition and free energy landscape (FEL) analyses. The two representative structures from the apo simulation are further subjected to MD simulation, followed by similar analyses. MD simulation analyses revealed the distinct modes of ligand interaction across the different monomeric forms, accompanied by extensive contacts with residues in the binding region. Therefore, our study, which provides insights for evaluating the efficacy of BMS-984923 to facilitate subsequent binding with the target protein, will offer a framework for the rational design of potential inhibitors against the pathogenic Aβ peptide.