Computational studies of mycobacterium tuberculosis L, d-transpeptidase2.
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Tuberculosis (TB) is still one of the most highly elusive lethal transmittable diseases to eradicate and persist to be a major threat to public health due to emergence of drug resistance. Drug-resistant is steadily increasing worldwide, therefore, there is an urgent need for development of improved efficacious antibiotics and novel drug targets to successfully contain the disease. Peptidoglycan layer (PG) is the major attribute in bacterial cell envelope and is essential for protection and growth in all bacterial species including Mycobacterium tuberculosis(Mtb). The biosynthesis pathway for PG is extremely intricate and involves numerous interconnected metabolites such as N-acetylmuramic(NAM) acid and N-acetylglucosamine(NAG), that are required during transpeptidation. These two sugar molecules are linked together by a β (1-4) glycosidic bond and the NAM attaches 3-5 amino acid peptide stems. Consequently, the peptidoglycan strands are cross linked by transpeptidases, namely D, D- and L, D-transpeptidases, forming crucial 4→3 and 3→3 cross-linkages respectively. Both D, D- and L, D-transpeptidases need to be inhibited concomitantly to eradicate the bacterium. L, D-transpeptidase 2 (LdtMt2) is one of the paralogs that is essential for Mtb growth, cell morphology and virulence during the chronic stage of the disease. This paralog has major influence in drug resistance and persistence of tuberculosis. The traditional β-lactam family of antibiotics have been reported to be effective against Mtb following the inactivation of β-lactamases (BlaC) known to rapidly hydrolyze the core β-lactam ring. The classic penicillins inhibit D, D-transpeptidases, while L, D transpeptidases are blocked by carbapenems. Despite several studies in this field, to the best of our knowledge, limited attention has been paid to the inhibition mechanism of LdtMt2 using carbapenem derivatives. In this regard, we need to explore reliable alternative strategies that are most cost-effective in terms of investigating the interactions of FDA approved carbapenems against Mtb L, D-Transpeptidases and study the role of explicit water molecule confined in the active site. As a result, computational chemistry has provided the possibility to sightsee and investigate this problem with relatively cost effective computational techniques. In this thesis, we applied a hybrid quantum mechanics and molecular mechanics techniques (QM:MM), Our own N-layered Integrated molecular Orbital and Molecular Mechanics (ONIOM) approach, to investigate the binding interaction energies of carbapenems (biapenem, imipenem, meropenem and tebipenem) against L, D-transpeptidase 2. Furthermore, the role of explicit water molecule confined in the active site was also explored using the same hybrid method to ascertain the nature of binding interaction energies of carbapenems against LdtMt2. In all the investigated carbapenem─LdtMt2 complexes, the carbapenems and the catalytic active site residues of LdtMt2 (Cys205, His187, Ser188, His203 and Asn207) were treated at QM (B3LYP/6-31+G(d)) level of theory whereas the remaining part of the complexes were treated at MM level (AMBER force field). The explicit water molecules near the carbapenems were considered and treated at QM as well. The obtained findings of Gibbs free energy (G), enthalpy (H) and entropy (S) for all studied complexes showed that the carbapenems exhibit reasonable binding interactions towards LdtMt2. This can be attributed by the structural dissimilarities of the carbapenems side chain which significantly induce conformational changes in the LdtMt2. In comparison, the binding free energy calculations of the model system with explicit water molecule yielded significant binding interaction energies. The QTAIM and NBO results confirmed the nature of binding free energies that the topological properties of atoms in molecules and the delocalization of electrons are from a bonding to antibonding orbitals in hydrogen bond interactions and this has enhanced the stability of carbapenem―LdtMt2 complexes. We believe that molecular insight of the carbapenems binding to LdtMt2 and the role of explicit solvent will enable us to understand the inhibition mechanisms.