Deciphering the dynamics of cathepsin D as a potential drug target to enhance anticancer drug-induced apoptosis

Abstract

The cathepsin D is a pepsin-family aspartic protease enzyme that is ubiquitous and is known for its vital role in tumor progression and metastasis. This study considered its therapeutic potential and aimed to employ a comprehensive computational approach to identify and understand possible inhibition mechanisms of drug molecules from the asinex database, comprehensive marine natural products database, and medicinal plant databases. By virtual screening of the said databases, three-hit molecules: hit-1 (2-(1-(4-fluoro-3-methylbenzoyl)pyrrolidin-3-yl)-4-hydroxy-6-(2-hydroxypyridin-1-ium-3-yl)pyrimidine-1,3-diium), hit-2 (4-(3-(3-(4-fluorophenyl)-1,7-dihydroimidazo[1,2-a]pyrimidin-8-ium-5-yl)-1H-pyrrol-1-yl)-2-methylpyrimidine-1,3-diium), and hit-3 (5-(1-(2-cyclopentylacetyl)pyrrolidin-2-yl)-3-(4-fluorophenyl)-1,7-dihydroimidazo[1,2-a]pyrimidin-8-ium) were identified against the cathepsin D enzyme. The compounds unveiled stable conformational dynamics and formed several key short-distance hydrophilic and hydrophobic interactions. It was found that hit-1, hit-2, and hit-3 molecules have a binding affinity of <−10 kcal/mol for the cathepsin D enzyme. Molecular dynamics simulation analysis examined the systems as significantly stable in terms of binding mode and chemical interactions. The system’s root mean square deviation (RMSD) in simulated time is <3 Å, which validates the docking and simulation data, binding free energies analysis including MM-GBSA, MM-PBSA, and WaterSwap analysis. The MM-GBSA analysis estimated −73.86, −75.8, and −87.02 net binding energies, while the MM-PBSA analysis estimated −70.58, −78.15, and −82.35 net free binding energies for Hit 1, Hit 2, and Hit 3, respectively. The binding interaction pointed towards stable interactions energy of compounds with cathepsin D, while the WaterSWAP analysis for the Hit-1 system, the Bennetts, FEP, and TI energy value is −36 kcal/mol, −37 kcal/mol, and −36 kcal/mol, respectively. The Hit-2 system has a binding energy of −39 kcal/mol (Bennetts), −39 kcal/mol (FEP), and −38 kcal/mol (TI). The Hit-3 complex was revealed to be more stable even than the control. The binding energy value of Bennetts, FEP, and TI is −42 kcal/mol, −41 kcal/mol, and −42 kcal/mol, respectively. Several hotspot residues were also highlighted in intermolecular interactions, and those, when mutated, impacted the overall binding energy of complexes. Lastly, the compounds were revealed to show favorable ADMET properties and thus could be regarded as promising leads for future experimental validation.