Docking And Molecular Dynamics Simulation Of Interactions Between Mycobacterium Tuberculosis BlaC, Ldt_Mt2 And Carbapenems

Three of the ten top-selling drugs in the United States are covalent inhibitors, showing its practical and theoretical research value. However, the conventional molecular docking softwares are not suitable to evaluate the covalent bond-contained receptor-ligand complexes. The interactions between Mycobacterium tuberculosis BlaC, LdtMt2 and carbapenems contain both covalent bond and non-covalent bond interactions. Using these systems, we are going to explore the appropriate computational approaches of covalent bond interaction in the drugs to help the drug discovery of the specific covalent bond drugs. This research article contains the following three parts:1, We combined the covalent and non-covalent docking algorithms to calculate four BlaC systems complexed with four carbapenems inhibitors. Firstly, the (3-lactam ring is opened and minimized using CovalentDock, followed by the structural modification for ring isomorization. Then, the B1aC residue Ser was replaced with Gly to eliminate the intermolecular covalent bond. For choosing a proper non-covalent docking tool, three softwares LeDock, AutoDock Vina and Lead Finder were tested and compared. LeDock performs better and was used in our approach which combines both non-covalent docking and covalent docking steps. Applying this approach to the four BlaC systems, the rank of the computed scores is consistent with that of the binding affinity values derived from the experimental Km data.2, In order to evaluate our combined method, MD simulations were performed to compare the crystal structures with the docked conformations using the modified structures without covalent bond. Furthermore, the energy contribution of each residue was computed by MM-GBSA method to investigate the inhibition differences of the four BlaC systems via analyzing their structures, binding modes and energy values. The detailed analysis shows that the interactions between the receptor and the ligands are affected by the LogP and the number of rotatable bonds, via changing several important factors including the hydrogen bond strength between BlaC and the ligands, the volume of active pocket and the binding free energy component of residues.3, The interaction between LdtMt2 and carbapenem meropenem was studied using MD simulations. The two-steps mechanism is presented via the flexible changes in the active site H-bonds and the catalytic region. This helps design new LdtMt2 inhibitors.This work provides a computational approach which combines the covalent bond docking and non-covalent bond docking algorithms to help design rational and specific covalent bond drugs.