From a Computational Perspective: Elucidating the Neurotherapeutic and Inhibitory properties of LRRK2 Kinase Domain by a benzothiazole-based compound.

Abstract

Parkinson's disease (PD) is one of the most prominent neurodegenerative diseases hence the continual search for viable and effective treatment options. The pathogeny of PD is driven by many key proteins among which is the recently identified Leucine-rich repeated kinase 2 (LRRK2). Going forward, the onus lies on identifying small-molecule inhibitors that can halt its pathogenic involvement, and, importantly, possess the capacity to cross the blood-brain barrier (BBB). Although several compounds have been identified over the past decade for their potencies, a major limitation remains the inability of the majority to cross the blood-brain barrier (BBB). A novel series of benzothiazole-based compounds with varying LRRK2 inhibitory activities were recently synthesized, with one compound 14 (CPD14) that notably inhibited LRRK2 and promoted neuronal progenitor proliferation. Here, we implemented molecular modelling and computational simulation methods to characterize CPD14 inhibitory mechanisms and dynamics against LRRK2. More so, we employed pharmacokinetic parameters to evaluate the biological activity and CNS-suitability of CPD14. Molecular dynamics evaluation revealed that CPD14 elicited disruptive effects on the secondary structure of LRRK2, including its catalytic kinase domain. Interaction analyses at the binding site further revealed crucial residues for the affinity binding and stability of CPD14, further supported by a highly favorable binding energy (ΔG). Pharmacokinetic predictions revealed the CNS-suitability of CPD14 based on its adherence to Lipinski's rule of 5 for neurogenic compounds. Also, CPD14 exhibited inhibitory tendencies against transcription proteins such as signal transducer and activation transcription (STAT) protein and STAT3; complementary mechanisms that could account for its in vitro potency. These findings, taken together, will aid the pharmacological and pharmacokinetic optimization of novel LRRK2 inhibitors for the treatment of PD.