Virtual Screening and Biological Activity Evaluation of New Potent Inhibitors Targeting LRRK2 Kinase Domain

Abstract

Leucine rich repeat kinase 2 (LRRK2) has been reported in the pathogenesis of Parkinson’s disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may provide new treatments for PD. In this study, novel LRRK2 inhibitors were identified by performing a docking-based virtual screening (VS). Due to the absence of a crystal structure of LRRK2, homology modeling was adopted to model human LRRK2 kinase domain that binds the inhibitor. Next, a docking-based virtual screening protocol was applied to identify LRRK2 small molecule inhibitors targeting the ATP binding pocket. A total of 28 compounds were selected and subjected to LRRK2 kinase inhibition assay. As a result, two small molecules with novel skeleton, compounds LY2019-005 and LY2019-006, were identified as potential LRRK2 kinase inhibitors with the IC50 of these two compounds against the wild-type and G2019S mutant LRRK2 kinase being 424.40 ± 1.31 nM, 378.80 ± 1.20 nM and 1526.00 ± 0.87 nM, 1165.00 ± 1.18 nM, respectively. Molecular dynamics (MD) simulation was carried out to reveal the binding mode of the newly identified compound LY2019-005 to the LRRK2 kinase domain. The binding modes indicate that the important hydrogen bond between hinge region (such as Ala1950) and inhibitor is crucial for the inhibition activity. In summary, our study provides a highly efficient way to discover LRRK2 inhibitors, and we find two highly efficient novel LRRK2 inhibitors, which could be helpful for the development of potential drugs targeting LRRK2 in PD therapy.

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

“…The ATP molecule interacts with Lys1906 and not with other important residues. None of the kinase domain–mutated residues forms interactions with the ATP molecule similar to the previous homology obtained structures [ 65 , 68 , 70 ]. The knowledge of the intermolecular interactions between the G2019S LRRK2 kinase domain and ATP may be critical for the development of G2019S-specific inhibitors over WT LRRK2 protein.…”

“…The knowledge of the active site of the enzyme is the basis for structure-based drug development. Previous structure-based studies used homology-based approaches to show the molecular details of the kinase domain [ 25 , 65 , 66 , 67 , 68 ]. Figure 2 A shows the recently published Cryo-EM structure of LRRK2 reported in the mutant G2019S form bound with ATP (PDB: 7LI3) [ 24 ].…”

Molecular Modeling Study on the Interaction Mechanism between the LRRK2 G2019S Mutant and Type I Inhibitors by Integrating Molecular Dynamics Simulation, Binding Free Energy Calculations, and Pharmacophore Modeling

“…Molecular docking was performed to predict the binding affinities using Glide SP docking precision within the software Schrödinger2015 Glide SP. First, the G2019S LRRK2 kinase domain was retrieved from three structures: one is from the crystal structure (PDB ID: 6VNO) with apo protein and mutated the corresponding amino acid in the wildtype (WT) LRRK2 complex through PyMOL (version 2.5.0) software; the second is from the structure (PDB ID: 7LI3) with the G2019S LRRK2 protein combined with ATP; and the third is from the cluster structure by homology modeling and 300 ns MD simulation from our previous work . The three proteins were prepared with Protein Preparation Wizard Workflow in Schrödinger2015.…”

Novel 1,2,3-Triazole Erlotinib Derivatives as Potent IDO1 Inhibitors: Design, Drug-Target Interactions Prediction, Synthesis, Biological Evaluation, Molecular Docking and ADME Properties Studies

“…The default parameters were used for ADME prediction in the normal mode ( Ibrahim et al, 2021 ). The following ADME properties were predicted, including partition coefficient (QPlogP octanol/water), predicted aqueous solubility (QPlogS), predicted brain/blood partition coefficient (QPlogBB), gut–blood brain barrier (QPPCaco), predicted IC 50 value for blockage of HERGK + channels (QPlogHERG), and predicted value of binding to human serum albumin (QPlogKhsa) ( Toppo et al, 2021 ; Tan et al, 2021 ).…”