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 Uet al.
2019 • In Journal of Molecular Modeling, 25 (11), p. 328
[en] 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. Graphical abstract.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sabe, Victor T; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
Tolufashe, Gideon F; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
Ibeji, Collins U; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
Maseko, Sibusiso Bonginkhost ; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
Govender, Thavendran; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
Maguire, Glenn E M; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa ; School of Chemistry and Physics, University of KwaZulu-Natal, Durban, 4001, South Africa
Lamichhane, Gyanu; Center for Tuberculosis Research, Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
Honarparvar, Bahareh; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa. Honarparvarb@ukzn.ac.za
Kruger, Hendrik G ; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa. kruger@ukzn.ac.za
Language :
English
Title :
Identification of potent L,D-transpeptidase 5 inhibitors for Mycobacterium tuberculosis as potential anti-TB leads: virtual screening and molecular dynamics simulations.
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