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

Victor T. Sabe, Gideon F. Tolufashe, Collins U. Ibeji, Sibusiso B. Maseko, Thavendran Govender, Glenn E.M. Maguire, Gyanu Lamichhane, Bahareh Honarparvar, Hendrik G. Kruger

Research output: Contribution to journalArticle

Abstract

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 (LdtMt5) and also an adduct of meropenem exhibited slow acylation. Since these drugs are active against L,D-transpeptidase 2 (LdtMt2), 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 LdtMt5. To further validate the obtained virtual screening ranking for LdtMt5, we screened the same libraries of compounds against LdtMt2 which had more experimetal and calculated binding energies reported. The observed consistency between the binding affinities of LdtMt2 validates the obtained virtual screening binding scores for LdtMt5. We subjected 37 compounds with docking scores ranging from − 7.2 to − 9.9 kcal mol−1 obtained from virtual screening for further MD analysis. A set of compounds (n = 12) from four antibiotic classes with ≤ − 30 kcal mol−1 molecular mechanics/generalized born surface area (MM-GBSA) binding free energies (ΔGbind) 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 LdtMt5. [Figure not available: see fulltext.].

Original languageEnglish (US)
Article number328
JournalJournal of Molecular Modeling
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2019

Fingerprint

Peptidyl Transferases
tuberculosis
inhibitors
Molecular dynamics
Screening
screening
molecular dynamics
Computer simulation
meropenem
doripenem
simulation
acylation
Lactams
Acylation
Carbapenems
Molecular mechanics
ranking
antibiotics
Antibiotics
Binding energy

Keywords

  • L,D-transpeptidase 5 (Ldt)
  • Molecular dynamics (MD)
  • Molecular mechanics/generalized born surface area (MM-GBSA)
  • Mycobacterium tuberculosis (M.tb)
  • Virtual screening

ASJC Scopus subject areas

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry

Cite this

Identification of potent L,D-transpeptidase 5 inhibitors for Mycobacterium tuberculosis as potential anti-TB leads : virtual screening and molecular dynamics simulations. / Sabe, Victor T.; Tolufashe, Gideon F.; Ibeji, Collins U.; Maseko, Sibusiso B.; Govender, Thavendran; Maguire, Glenn E.M.; Lamichhane, Gyanu; Honarparvar, Bahareh; Kruger, Hendrik G.

In: Journal of Molecular Modeling, Vol. 25, No. 11, 328, 01.11.2019.

Research output: Contribution to journalArticle

Sabe, Victor T. ; Tolufashe, Gideon F. ; Ibeji, Collins U. ; Maseko, Sibusiso B. ; Govender, Thavendran ; Maguire, Glenn E.M. ; Lamichhane, Gyanu ; Honarparvar, Bahareh ; Kruger, Hendrik G. / Identification of potent L,D-transpeptidase 5 inhibitors for Mycobacterium tuberculosis as potential anti-TB leads : virtual screening and molecular dynamics simulations. In: Journal of Molecular Modeling. 2019 ; Vol. 25, No. 11.
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