Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA₂, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA₂ to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA₂, and the optimal linker will enable maximal PLA₂-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA₂ transition state binding free energy of the prodrug molecule (∆∆G^tr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA₂-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.