The single crystal X-ray structure of the extracellular portion of the 3,3-transpeptidase (ex-LdtMt2 - residues 120 - 408) enzyme was recently reported. It was observed that imipenem and meropenem inhibit activity of this enzyme, responsible for generating 3,3-transpeptide linkages in the peptidoglycan layer of Mycobacterium tuberculosis. Imipenem is more active and isothermal titration calorimetry (ITC) experiments revealed that meropenem is subjected to an entropy penalty upon binding to the enzyme. Herein we report a molecular modelling approach to obtain a molecular view of the inhibitor/enzyme interactions. The average binding free energies for nine commercially available inhibitors were calculated using MM/GBSA and SIE approaches and the calculated energies corresponded well with the available experimentally observed results. The method reproduces the same order of binding energies as experimentally obesreved for imipenem and meropenem. We have also demonstrated that SIE is a reasonable accurate and cost effective free energy method, which can be used to predict carbapenem affinities for this enzyme. A theoretical explanation was offered for the experimental entropy penalty observed for meropenem, creating optimism that this computational model can serve as a potential computational model for other researchers in the field.