Identification of novel anti‐Alzheimer’s drugs through inhibition of LRP‐DKK interaction: A computational approach using high throughput virtual screening and molecular dynamics studies

Abstract

AbstractBackgroundActivation of WNT signalling pathway was involved in a neuroprotective mechanism against amyloid beta toxicity (1). Inhibition of this pathway is associated with GSK‐3 beta activation, tau hyperphosphorylation, neuronal apoptosis (1), (2) and is implicated in Alzheimer’s disease (1). DKK‐1 competes with Wnt for the binding to LRP5/6 receptor (3) and disrupts the Wnt‐induced Fzd‐Wnt‐LRP6 complex (4) and thus antagonizes the neuro‐protective effect of WNT. In this study, we have targeted the DKK‐LRP interaction through virtual screening the first time to develop novel anti‐Alzheimer’s agent.MethodBased upon crystal structure information and protein validation using Ramachandran Plots, a crystal structure (PDB: 3S8V) was selected for further works. In this study, we have targeted the surface of LRP 5/6, which is interacting with DKK and grid was generated on LRP. The virtual screening of Asinex database library (N=19642) was done against this grid. Molecules were selected on the basis of good dock score and binding free energy calculation using MMGBSA in Schrodinger GLIDE (5)(6). The protein ligand complex structure stability were also evaluated by molecular dynamic simulation study (7). ADMET profile of the screened ligands were evaluated using Quick prop module of Schrodinger.ResultAfter running the virtual screening protocol (HTVS: SP: XP), 14 compounds were screened out, which showed significant binding top the DKK1 binding interface of LRP. These compounds were further evaluated on basis of docking score and MMGBSA. On the basis of After then on the basis of ADME profile selected 2 compound id ZINC000100138828 and ZINC000247940500 for further molecular dynamic simulation study which were shown the compound ZINC000100138828 had an avg. RMSD of ∼4.0Å, also the RMSF is 2.4 Å for overall protein side chain residue was reduced with reference to the apo form. It is displays rich interaction profile and strength with core binding residues (A: Pro833, B: Tyr706, B: Glu708, B: Arg751 and B: Ile681).ConclusionZINC000100138828 is a potent binder to the DKK1 binding surface on LRP5/6. It needs further in‐vitro and preclinical validation as a potential anti‐Alzheimer’s agent.