Molecular docking of analogues linezolid

Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It appeared on the market in 2000 for treatment of infections caused by streptococci, vancomycin-resistant enterococci, and methicillin-resistant Staphylococcus aureus. Linezolid acts as a protein synthesis inhibitor by binding to the ribosomal peptidyl transferase center and stopping the growth of bacteria [1]. In vitro and in vivo assays of oxazolidinone analogues show that the structural features to have a good biological activity and pharmacokinetic properties are: 1) an N-aryl group, 2) a (5S)-absolute configuration, 3) the preference for a C-5 acetamidomethyl side chain, 4) unsaturated or electron-withdrawing groups in the para position of the N-aryl ring generally potentiate activity but an electron-donating amino substituent in the para position on the phenyl ring can confer a good safety profile, 5) additional substitutions on the proximal aromatic ring or a C-4 or C-5 of the oxazolidinone ring usually a detrimental or at best, indifferent effect on the antibacterial activity, 6) one or two fluorine atoms on the phenyl ring usually exerts a significant potentiating effect on efficacy [2]. However the rising resistance to linezolid of some bacterial strains necessitates the discovery of novel biological active molecules. In this study we elucidate the binding mode of linezolid and its analogues in the apo and holo ribosomal subunit of Haloarcula Marismortui bacterium with the molecular docking software AutoDock 4.2 [3]. The ligands chosen are three commercial oxazolidinone compounds (posizolid, eperezolid, torezolid) in which morpholino ring and acetamidomethyl residue are replaced and four new-synthesized molecules in which the oxazolidinone ring is replaced. Early work in this area identified suitable bioisosteric replacement for the usual oxazolidinone ring was: 1) a 5-membered ring appears optimal, 2) a sp2 center adjacent to the phenyl ring, 3) an oxygen atom strategically bound, 4) a chiral center of appropriate absolute configuration. Since these above principles, the isoxazolidinone and dihydropyrrole rings have been chosen like suitable ring replacements [2]. The ligands have on C-4 position ring isopropyl and cyclohesyl substituents. These ligands have been synthesized for the first time in the Alessandra Tolomelli's laboratory (Department of Chemistry "G. Ciamician" University of Bologna, Italy). Docked posizolid molecule in the holo ribosomal binding site. The 5-membered ring orients toward the ribosomal tunnel whereas 2,3 dihydroxyacetone is toward the intersubunit interface. Within the pocket the oxazolidonone ring is stacked against the base moiety of U2539. The dihydroxyacetone OH groups participate in hydrogen bonds with the ribose group of U2541 and U2619. The fluorophenyl moiety makes stacking interaction with the residues A2486 and C2487, whereas the tetrahydropyridine ring does not appear to make significant interactions with the ribosome. The obtained results for each ligand are presented and discussed. The predictions show good reliability for the holo receptor but produce substantially different results for apo one. This is probably due to the complexity of the receptor, formed by proteins and nucleic acids. We are thus improving the docking scheme by including some degrees of flexibility in the receptor and by testing different docking algorithms. These tasks are currently being addressed in our laboratories. [1] J.A. Ippolito, Z. Kanyo, D. Wang, F. Franceschi, P. Moore, T. Steitz, and E. Duffy, Journal medical chemistry, 2008, 51, 3353-3356. [2] Antibiotic discovery and development. T.J. Dougherty, and M.J. Pucci, Michael, Springer ed., 2012, XVll, 273-293. [3] Journal of computational chemistry R. Huey, G. Morris, and A. Olson, D. Goodsell, 2007, 28, 1145-1152.