We used RxDock to dock compounds 15, 20, and 22 to carbonic anhydrases I, II, IX, and XII to inspect the consensus of their interaction with the aforementioned inhibitory mechanism of coumarin inhibitors. The top docked poses of our intact inhibitors indeed displayed remarkable consistency with the suicide inhibition mechanism of coumarin inhibitors, where the vulnerable lactone ring aligned repeatedly to the vicinity of the catalytic zinc ready to be hydrolyzed (Figures ). On the other hand, the poses of our hydrolyzed inhibitors were sparingly harmonious unveiling the highly dynamic and exceedingly complex nature of those peculiar suicide inhibitors. Hence, we refrained from drawing insights based on those hydrolyzed poses until we further investigate them using in-depth hybrid QM/MM simulations in future studies. Metalloenzymes are frequently challenging in molecular modeling studies because of the difficulties inherent to the parameterization of metal atoms in most force fields; results may incur deviations if these parameters are overlooked . Ergo to properly examine any potential interactions between our compounds and the catalytic zinc center of the enzyme, we supplied the RxDock scoring function with additional parameters based on the Sybyl-X 2.1 Tripos 5.2 force field to enhance the scoring function's definition of this charged metal atom. In addition, we selected four PDB entries (PDB IDs: 1AZM, 3HS4, 3IAI, and 1JD0) sharing the same co- crystallized inhibitor "Acetazolamide" to standardize our control ligand across the four enzyme isoforms during the validation procedure of the docking protocol. Moreover, we thoroughly validated the docking protocol by implementing an exhaustive search for the optimal random seed, to initiate the rbdock program, which resulted in the best RMSD values per each of the four PDB crystal structures upon redocking of its co-crystallized Acetazolamide. These four optimal random seeds were then used to dock our compounds to the four carbonic anhydrases respectively, along with all the other validated parameters of the docking protocol maintained.