Evaluating the covalent binding of carbapenems on BlaC using noncovalent interactions

Lu Sun,Shijun Zhong,Hongjun Fan

doi:10.1007/s00894-021-04760-x

Abstract

Carbapenems, as irreversible covalent binders and slow substrates to the class A β-lactamase (BlaC) of Mycobacterium tuberculosis, can inhibit BlaC to hydrolyze the β-lactam drugs which are used to control tuberculosis. Their binding on BlaC involves covalent bonding and noncovalent interaction. We introduce a hypothesis that the noncovalent interactions dominate the difference of binding free energies for covalent ligands based on the assumption that their covalent bonding energies are the same. MM/GBSA binding free energies calculated from the noncovalent interactions provided a threshold with respect to the experimental kinetic data, to select slow carbapenem substrates which were either constructed using the structural units of experimentally identified carbapenems or obtained from the similarity search over the ZINC15 database. Combining molecular docking with consensus scoring and molecular dynamics simulation with MM/GBSA binding free energy calculations, a computational protocol was developed from which several new tight-binding carbapenems were theoretically identified.

Highlights

Mycobacterium tuberculosis, a pathogenic bacterial species in the family of Mycobacteriaceae, causes tuberculosis which is one of the top 10 causes of death and makes millions of people fall sick each year.[1]
The basic process is that molecular dynamics (MD) simulations and binding free energy calculations performed on the by Class A β-lactamase (BlaC)-carbapenem systems (Fig. 3) can provide a threshold for selecting hits
The similarity search and combinations of structural units can be used to build new ligands which will be estimated using a series of computational treatments including molecular docking with consensus scoring and MD simulations with binding free energy calculations

Summary

Introduction

Mycobacterium tuberculosis, a pathogenic bacterial species in the family of Mycobacteriaceae, causes tuberculosis which is one of the top 10 causes of death and makes millions of people fall sick each year.[1] This is complicated by the emergence of multidrug-resistant and extensive drug-resistant strains of Mycobacterium tuberculosis, which reveals the drawback of the current treatment strategies for tuberculosis.[1,2,3] The β-lactam class of antibiotics such as penicillin were effective in the treatment of tuberculosis due to their inhibition of bacterial cell wall synthesis.[4] the efficacy is reduced due to the resistance caused by Class A β-lactamase (BlaC) which inactivates the β-lactam antibiotics via serine acylation followed by hydrolytic deacylation.[5] This involves the nucleophilic attack of the serine residue against the β-lactam carbonyl to form a covalent acyl-enzyme complex while the β-lactam ring is opened,[6] followed by the hydrolysis of the ester bond to release the inactive ring-opened product.[7] In order to Carbapenems contain the β-lactam ring and can be used as antibiotics targeting penicillin-binding proteins.[10] They are poor substrates with slow hydrolysis on BlaC and could act as inhibitor of BlaC or an active partner with inhibitor clavulanate[9] such that they may act as a template for the development of novel inhibitor combinations. All carbapenems have the same core structure but different R groups

Methods

Results

Conclusion