Objective: To validate effect of Indolocarbazole derivatives on Cyclin dependent kinase for treating Parkinson’s (Preliminary work in context of CDK5 assay and Simulations have been promising)

Background: Parkinson’s disease (PD), is a neurodegenerative disorder characterized by disabling motor abnormalities, including tremor, muscle rigidity, paucity of voluntary movements, and postural instability . Current treatment strategies for PD consist primarily of dopamine replacement therapy with levodopa or dopamine agonists. Uncontrolled up regulation of CDK5 by the shortened activators paves the way for neurodegeneration by changing the phosphorylation state of cytoskeletal and cytosolic proteins. This increased CDK5 activity is implicated in Parkinson’s

Methods: As ninety percent of kinomeee is durable by approved staurosporines.To understand the dynamics and binding affinity of Indolocarbazole derivatives (synthetic) in depth, biomolecular modeling and Dynamic simulation studies were performed and results were compared with known approved drug as well as apo protein.

Results: Structural deviation of these complex as well as Apo protein were analyzed using root mean square deviation of overall protein (RMSD), residue wise root mean square fluctuation (RMSF) and radius of gyration (RGYR) from 40 ns simulated trajectories . RMSD suggests that after 25 ns, all complexes ( Approved drug-Roscovitine & Indolocarbazole, complex) and free protein got stablized and structural deviations had converged.

Conclusions: The binding modes of Cyclin Dependent Kinase inhibitors were explored using biomolecular modelling and dynamic simulations. Modelling studies revealed that one of the Indolocarbazole derivative bind to the CDK5/p25 at crucial active site residues, and have favorable hydrogen bonding cum hydrophobic interaction with catalytic site bearing Cys 83. Molecular dynamic simulation studies of CDK5/p25 complexes suggests existence of ligand induced conformational changes in active site loop, which paves opening of active site for substrate recognition. We project these findings hold potential for development of novel PD therapeutic strategies.

References: Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shaw, D. E.; Shelley, M.; Perry, J. K.; Francis, P.; Shenkin, P. S., “Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy,” J. Med. Chem., 2004, 47, 1739–1749.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-mechanistic-involved-in-targeting-parkinsons-disease-by-indolocarbazole-derivatives-as-inhibitors-against-cyclin-dependent-kinases-using-molecular-modelling-and-simulation-approaches/