Molecular Docking and Molecular Dynamics Studies: Evaluation of the Potential Interaction between Ciprofloxacin-DAB-PAMAM Dendrimer-Based Prodrug Prototypes and Human Carboxylesterase 1

Abstract Ciprofloxacin is widely used as a drug for broad-spectrum treatment of infections. However, it is classified as class IV by the Biopharmaceutics Classification System, being characterized by low solubility and permeability. Aiming to contribute to the rational design that may improve the biopharmaceutical properties to increase drug efficacy, two series of prototypical compounds were designed: (1) ciprofloxacin prodrugs and (2) ciprofloxacin dendrimer prodrugs. Thus, this study performed molecular docking and molecular dynamics (MD) simulations to evaluate the interaction between the designed ligands and human carboxylesterase 1 (2H7C), focusing on comparing the results from both series of selected ligands. Additionally, nonspecific esterase was chosen due to its ability to cleave ester bonds in vivo, releasing the bioactive compound. The molecular docking results pointed out that the distance between the carbonyl group and Ser221 was shorter for Compounds 1 (dock 19: 2.2 Å) and 4 (dock 12: 1.8 Å). The MD simulations produced reasonable receptor-ligand complex interactions, which can be observed from the RMSD analysis showing significantly different trajectories with average atomic positions varying from 1.6 to 2.5 Å. Through the MD trajectories, the Potential Energy of Interaction (PEI) average values, ranging from −281.6 kJ/mol up to −1061.9 kJ/mol, showed strong interaction between the ciprofloxacin ligands and the Ser221 active site together with the MM/PBSA results. The findings indicated that the larger prodrug generations increased general receptor-ligand interaction and also specific ligand-SER interaction; thus, these findings demonstrate the potential of ciprofloxacin nanocompounds as a rationally designed treatment for infectious diseases.