Transmembrane protease serine 2 (TMPRSS2) is an important drug target due to its role in the infection mechanism of coronaviruses including SARS-CoV-2. Current understanding regarding the molecular mechanisms of known inhibitors and insights required for inhibitor design are limited. This study investigates the effect of inhibitor binding on the intramolecular backbone hydrogen bonds (BHBs) of TMPRSS2 using the concept of hydrogen bond wrapping, which is the phenomenon of stabilization of a hydrogen bond in a solvent environment as a result of being surrounded by non-polar groups. A molecular descriptor which quantifies the extent of wrapping around BHBs is introduced for this. First, virtual screening for TMPRSS2 inhibitors is performed by molecular docking using the program DOCK 6 with a Generalized Born surface area (GBSA) scoring function. The docking results are then analyzed using this descriptor and its relationship to the solvent-accessible surface area term ΔGsa of the GBSA score is demonstrated with machine learning regression and principal component analysis. The effect of binding of the inhibitors camostat, nafamostat, and 4-guanidinobenzoic acid (GBA) on the wrapping of important BHBs in TMPRSS2 is also studied using molecular dynamics. For BHBs with a large increase in wrapping groups due to these inhibitors, the radial distribution function of water revealed that certain residues involved in these BHBs, like Gln438, Asp440, and Ser441, undergo preferential desolvation. The findings offer valuable insights into the mechanisms of these inhibitors and may prove useful in the design of new inhibitors.