ORIGINAL PAPER 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 1 & Gideon F. Tolufashe 1 & Collins U. Ibeji 1 & Sibusiso B. Maseko 1 & Thavendran Govender 1 & Glenn E. M. Maguire 1,2 & Gyanu Lamichhane 3 & Bahareh Honarparvar 1 & Hendrik G. Kruger 1 Received: 5 October 2018 /Accepted: 28 August 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 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 (Ldt Mt5 ) and also an adduct of meropenem exhibited slow acylation. Since these drugs are active against L,D-transpeptidase 2 (Ldt Mt2 ), 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 Mt5 . To further validate the obtained virtual screening ranking for Ldt Mt5 , we screened the same libraries of compounds against Ldt Mt2 which had more experimetal and calculated binding energies reported. The observed consistency between the binding affinities of Ldt Mt2 validates the obtained virtual screening binding scores for Ldt Mt5 . 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 (ΔG bind ) 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 Mt5 . Keywords Virtual screening . Molecular dynamics (MD) . Mycobacterium tuberculosis (M.tb) . L,D-transpeptidase 5 (Ldt Mt5 ) . Molecular mechanics/generalized born surface area (MM-GBSA) Introduction The alarming rise of multi and extensively drug-resistant tuber- culosis (TB) has become a serious global health threat [1]. The emergence of resistant strains is partly due to poor patient com- pliance to the extensive treatment regimen [2, 3]. Thus, the iden- tification of new anti-TB leads, particularly Ldt Mt5, that can short- en the treatment regimen and target the resistant TB strains is urgently needed. Mycobacterium tuberculosis possesses a pepti- doglycan (PG) layer that encapsulates the cytoplasmic mem- brane and is essential for cellular growth and viability [ 4]. The peptidoglycan structure of Mycobacterium tuberculosis (M.tb) from a stationary-phase culture revealed a high content (80%) of non-classical 3 → 3 cross-links generated by L,D- transpeptidation [5]. The classical 4 → 3 cross-links are predom- inantly formed by the D,D-transpeptidation activity of penicillin- binding proteins (PBPs) during the exponential phase of growth [6–9]. L,D-transpeptidases (Ldts) and PBPs are structurally Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-019-4196-z) contains supplementary material, which is available to authorized users. * Bahareh Honarparvar Honarparvarb@ukzn.ac.za * Hendrik G. Kruger kruger@ukzn.ac.za 1 Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa 2 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa 3 Center for Tuberculosis Research, Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA Journal of Molecular Modeling (2019) 25:328 https://doi.org/10.1007/s00894-019-4196-z