Identification of potent L,D-transpeptidase 5 inhibitors for Mycobacterium tuberculosis as potential anti-TB leads: virtual screening and molecular dynamics simulations.

Virtual screening is a useful in silico approach to identify potential leads against various targets. It is known that carbapenems (doripenem and faropenem) do not show any reasonable inhibitory activities against L,D-transpeptidase 5 (Ldt) and also an adduct of meropenem exhibited slow acylation. Since these drugs are active against L,D-transpeptidase 2 (Ldt), understanding the differences between these two enzymes is essential. In this study, a ligand-based virtual screening of 12,766 compounds followed by molecular dynamics (MD) simulations was applied to identify potential leads against Ldt. To further validate the obtained virtual screening ranking for Ldt, we screened the same libraries of compounds against Ldt which had more experimetal and calculated binding energies reported. The observed consistency between the binding affinities of Ldt validates the obtained virtual screening binding scores for Ldt. We subjected 37 compounds with docking scores ranging from - 7.2 to - 9.9 kcal mol obtained from virtual screening for further MD analysis. A set of compounds (n = 12) from four antibiotic classes with ≤ - 30 kcal mol molecular mechanics/generalized born surface area (MM-GBSA) binding free energies (ΔG) was characterized. A final set of that, all β-lactams (n = 4), was considered. The outcome of this study provides insight into the design of potential novel leads for Ldt. Graphical abstract.