Catalyzing a Cure: Discovery and development of LRRK2 inhibitors for the treatment of Parkinson's disease.

Parkinson's disease (PD) is an age-related second most common progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no effective disease modifying therapeutics have reached clinics for treatment/management of PD. Leucine-rich repeat kinase 2 (LRRK2) which controls membrane trafficking and lysosomal function and its variant LRRK2-G2019S are involved in the development of both familial and sporadic PD. LRRK2, is therefore considered as a legitimate target for the development of therapeutics against PD. During the last decade, efforts have been made to develop effective, safe and selective LRRK2 inhibitors and also our understanding about LRRK2 has progressed. However, there is an urge to learn from the previously designed and reported LRRK2 inhibitors in order to effectively approach designing of new LRRK2 inhibitors. In this review, we have aimed to cover the pre-clinical studies undertaken to develop small molecule LRRK2 inhibitors by screening the patents and other available literature in the last decade. We have highlighted LRRK2 as targets in the progress of PD and subsequently covered detailed design, synthesis and development of diverse scaffolds as LRRK2 inhibitors. Moreover, LRRK2 inhibitors under clinical development has also been discussed. LRRK2 inhibitors seem to be potential targets for future therapeutic interventions in the treatment and management of PD and this review can act as a cynosure for guiding discovery, design, and development of selective and non-toxic LRRK2 inhibitors. Although, there might be challenges in developing effective LRRK2 inhibitors, the opportunity to successfully develop novel therapeutics targeting LRRK2 against PD has never been greater.

Anti-Alzheimer activity of new coumarin-based derivatives targeting acetylcholinesterase inhibition.

New 2-oxo-chromene-7-oxymethylene acetohydrazide derivatives 4a-d were designed and synthesized with a variety of bioactive chemical fragments. The newly synthesized compounds were evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents in comparison to donepezil and ascorbic acid, respectively. Compound 4c exhibited a promising inhibitory impact with an IC50 value of 0.802 µM and DPPH scavenging activity of 57.14 ± 2.77%. Furthermore, biochemical and haematological studies revealed that compound 4c had no effect on the blood profile, hepatic enzyme levels (AST, ALT, and ALP), or total urea in 4c-treated rats compared to the controls. Moreover, the histopathological studies of 4c-treated rats revealed the normal architecture of the hepatic lobules and renal parenchyma, as well as no histopathological damage in the examined hepatic, kidney, heart, and brain tissues. In addition, an in vivo study investigated the amelioration in the cognitive function of AD-rats treated with 4c through the T-maze and beam balance behavioural tests. Also, 4c detectably ameliorated MDA and GSH, reaching 90.64 and 27.17%, respectively, in comparison to the standard drug (90.64% and 35.03% for MDA and GSH, respectively). The molecular docking study exhibited a good fitting of compound 4c in the active site of the AChE enzyme and a promising safety profile. Compound 4c exhibited a promising anti-Alzheimer's disease efficiency compared to the standard drug donepezil.

Structure-based virtual screening for identification of potential non-steroidal LXR modulators against neurodegenerative conditions.

Liver X Receptors (LXRs) are members of the nuclear receptor superfamily that regulate cholesterol metabolism. LXRs have been suggested as promising targets against many neurodegenerative diseases (NDDs). The present study was aimed to identify novel non-steroidal molecules that may potentially modulate LXR activity. The structure-based virtual screening (SBVS) was used to search for suitable compounds from the Asinex library. The top hits were selected and filtered based on their binding affinity for LXR α and ß isoforms. Based on molecular docking and scoring results, 24 compounds were selected that had binding energy in the range of - 13.9 to - 12 for LXRα and - 12.5 to - 11 for LXRß, which were higher than the reference ligands (GW3965 and TO901317). Further, the five hits referred to as model 29, 64, 202, 250, 313 were selected by virtue of their binding interactions with amino acid residues at the active site of LXRs. The selected hits were then subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis and blood-brain permeability prediction. It was observed that the selected hits had better pharmacokinetic properties with no toxicity and could cross blood-brain barrier. Further, the selected hits were analysed for dynamic evolution of the system with LXRs by molecular dynamics (MD) simulation at 100 ns using GROMACS. The MD simulation results validated that selected hits possess a remarkable amount of flexibility, stability, compactness, binding energy and exhibited limited conformational modification. The root mean square deviation (RMSD) values of the top-scoring hits complexed with LXRα and LXRß were 0.05-0.6 nm and 0.05-0.45 nm respectively, which is greater than the protein itself. Altogether the study identified potential non-steroidal LXR modulators that appear to be effective against various neurodegenerative conditions involving perturbed cholesterol and lipid homeostasis.