Computational insights into the protonation states of catalytic dyad in BACE1–acyl guanidine based inhibitor complex

Developing small compound based drugs targeting the β-secretase (BACE) enzyme is one of the most promising strategies in treatment of the Alzheimer’s disease. As the enzyme shows the activity based on the acid-base reaction at a very narrow pH range, the protonation state of aspartic acids with the residue number 32 and 228 (Asp32 and Asp228), which forms the active site dyad, along with the protonation state of the ligand (substrate or inhibitor) play very critical role in interactions between the ligand and enzyme. Thus, understanding the nature of the protonation state of both enzyme’s active site dyad and ligand is crucial for drug design in Alzheimer’s disease field. Here we have investigated the protonation state of the Asp32 and Asp228 residues in the presence of a highly potent beta secretase inhibitor, containing acyl guanidine warhead that have recently been devised but not extensively studied. Our Quantum Mechanical, Molecular Dynamics and Docking studies on all the possible protonation states have suggested that the dyad residues are in di-deprotonated states in the presence of protonated inhibitor.