RESUMEN
The present study was initiated with PDB selection and validation where 11 acetylcholinesterase (AChE) and 4 N-methyl-D-aspartate receptor (NMDAR) proteins were considered for docking with Rivastigmine and Riluzole respectively. Out of the 15 proteins, selected significant binding was observed for AChE, with 5FPQ, and NMDA receptors with 5I2K. Molecular docking studies of 5FPQ/Rivastigmine complex displayed a binding score of -8.6 kcal/mol, and the predicted inhibitory concentration (Ki) was found to be 31 nM, whereas the 5I2K/Riluzole complex showed a binding score of -9.6 kcal/mol, with an inhibitory concentration (Ki) of 21 nM. Riluzole in complex with 5I2K formed predominant π-π stacking interactions with Tyr144, pi-alkyl interaction with Pro129, and conventional hydrogen bond with Phe130. In contrast, Rivastigmine in a complex with 5FPQ formed a hydrogen bond with Gln413 and pi-alkyl with Pro537. Molecular dynamics simulation study of both complexes 5FPQ/Rivastigmine and 5I2K/Riluzole exhibited stable RMSD, RMSF, Rg, and significant numbers of hydrogen bonds. From free energy landscape (FEL) analysis both complexes were observed to achieve global minima. Overall, molecular docking and MD simulation with subsequent binding free energies studies (MM-PBSA) elucidate the binding conformations and stability of these reprogrammed drugs in the AChE and NMDAR targets. From these in-silico predictions, it can be suggested that both Rivastigmine and Riluzole combination may provide better insights as a starting point combination therapy for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Enfermedad de Alzheimer , Simulación de Dinámica Molecular , Humanos , Rivastigmina/farmacología , Rivastigmina/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Acetilcolinesterasa/química , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/uso terapéutico , Inhibidores de la Colinesterasa/química , Riluzol/farmacología , Riluzol/uso terapéutico , Simulación del Acoplamiento MolecularRESUMEN
Aß cascade hypothesis being considered most evident event in AD pathology and even today it holds good. Dysregulation of catalytic events of Aß regulating enzymes can possibly cause faulty Aß trafficking; inequity of Aß formation and clearance resulting in misfolded protein accumulation, neurodegeneration and cognitive impairment. Many novel approaches have been made on this pathway to discover new molecules, unfortunately couldn't reach the terminal phases of clinical trials. Over decades, studies have been more focused on enzyme chemistry and explored the relationship between structural features and catalytic function of Aß regulating enzymes. However, the modulations of catalytic mechanisms of those enzymes have not been imposed so far to reduce the Aß load. Hence, in this review, we have critically detailed the knowledge of basic structural dynamics and possible catalytic modulations of enzymes responsible for Aß formation and clearance that will impart new perspectives in drug discovery process.