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.

Design, synthesis, biological evaluation and molecular dynamics of some novel 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based compounds as anti-tubercular agents.

Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) is a druggable target which is being exploited for the development of new anti-TB agents. In the present work, we report developing a pharmacophore model and performing virtual screening of Asinex database using the developed pharmacophore model to get eight hits as potential DprE1 inhibitors. The hits were used as leads to design new 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based potential anti-TB agents. On the basis of the identified lead molecules, a total of 18 compounds were synthesized and evaluated for their anti-TB activity by using MABA. ADMET predictions for all the compounds revealed that these compounds have drug-like and lead-like properties. One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis.Communicated by Ramaswamy H. Sarma.

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.

Allosteric Binding Sites of Aß Peptides on the Acetylcholine Synthesizing Enzyme ChAT as Deduced by In Silico Molecular Modeling.

The native function of amyloid-ß (Aß) peptides is still unexplored. However, several recent reports suggest a prominent role of Aß peptides in acetylcholine homeostasis. To clarify this role of Aß, we have reported that Aß peptides at physiological concentrations can directly enhance the catalytic efficiency of the key cholinergic enzyme, choline acetyltransferase (ChAT), via an allosteric interaction. In the current study, we further aimed to elucidate the underlying ChAT-Aß interaction mechanism using in silico molecular docking and dynamics analysis. Docking analysis suggested two most probable binding clusters on ChAT for Aß40 and three for Aß42. Most importantly, the docking results were challenged with molecular dynamic studies of 100 ns long simulation in triplicates (100 ns × 3 = 300 ns) and were analyzed for RMSD, RMSF, RoG, H-bond number and distance, SASA, and secondary structure assessment performed together with principal component analysis and the free-energy landscape diagram, which indicated that the ChAT-Aß complex system was stable throughout the simulation time period with no abrupt motion during the evolution of the simulation across the triplicates, which also validated the robustness of the simulation study. Finally, the free-energy landscape analysis confirmed the docking results and demonstrated that the ChAT-Aß complexes were energetically stable despite the unstructured nature of C- and N-terminals in Aß peptides. Overall, this study supports the reported in vitro findings that Aß peptides, particularly Aß42, act as endogenous ChAT-Potentiating-Ligand (CPL), and thereby supports the hypothesis that one of the native biological functions of Aß peptides is the regulation of acetylcholine homeostasis.