Computational Evaluation of Molecular Docking and Molecular Dynamic, Study of New Acyloxyalkyl Carbamates Prodrug Derivatives of Fluoxetine

ABSTRACT To evaluate the possible actions of five novels' fluoxetine prodrug derivatives, a number of them have been suggested. The prodrug method aims to increase the number of biopharmaceutical drug deliveries and the drug's pharmacokinetics and/or bioavailability. This strategy has additional benefits, such as therapeutic targeting by enzyme-triggered drug release. The extent of butyrylcholine esterase-mediated activation can be predicted using computational models, which also aid in the development of prodrugs. A variety of computational techniques, such as molecular docking and molecular dynamics simulations, which determined the binding affinities of the five fluoxetine prodrug derivatives molecules to the enzyme binding site by docking them. Computer simulations were performed with GOLD program (CCDC) version 5.43, and the compounds were created with ChemDraw version 22.2 (professional version). They were then evaluated for selectivity with BChE, and a control for comparison was butyrylthiocholine. and for 1nanosecond, SiBioLead server was used to run molecular dynamic simulations of compound A1 complexes with BChE enzyme. RMSD, RMSF, RG results, SASA result, and enzyme energy were estimated during this time. Results showed that the prodrug was activated by BChEenzyme, demonstrating the highest binding energy inside the active cite of the enzyme. PLP fitness values of 86.65, 80,81, and 82.819 were recorded by compounds A1, A2, and A4. This study reveals that fluoxetine prodrug molecular design guided by computational simulations can be more mechanistic and less empirical. Moving forward, the earliest possible stage in the development process should be when prodrugs' action is predicted by molecular modeling tools.