Quantum mechanical studies of lincosamides

Abstract

Lincosamides are a class of antibiotics used both in clinical and veterinary practice for a wide range of pathogens. This group of drugs inhibits the activity of the bacterial ribosome by binding to the 23S RNA of the large ribosomal subunit and blocking protein synthesis. Currently, three X-ray structures of the ribosome in complex with clindamycin are available in the Protein Data Bank, which reveal that there are two distinct conformations of the pyrrolidinyl propyl group of the bound clindamycin. In this work, we used quantum mechanical methods to investigate the probable conformations of clindamycin in order to explain the two binding modes in the ribosomal 23S RNA. We studied three lincosamide antibiotics: clindamycin, lincomycin, and pirlimycin at the B3LYP level with the 6-31G** basis set. The focus of our work was to connect the conformational landscape and electron densities of the two clindamycin conformers found experimentally with their physicochemical properties. For both functional conformers, we applied natural bond orbital (NBO) analysis and the atoms in molecules (AIM) theory, and calculated the NMR parameters. Based on the results obtained, we were able to show that the structure with the intramolecular hydrogen bond C=O…H–O is the most stable conformer of clindamycin. The charge transfer between the pyrrolidine-derivative ring and the six-atom sugar (methylthiolincosamide), which are linked via an amide bond, was found to be the dominant factor influencing the high stability of this conformer.FigureMolecular graph of more stable conformer of clindamycin.

Molecular dynamics simulations suggest why the A2058G mutation in 23S RNA results in bacterial resistance against clindamycin

“…6). Two clindamycin conformers differing in this dihedral were previously observed in the ribosome crystal structures in complexes with clindamycin [21, 22], in docking studies [25], and also by us in the simulations of clindamycin without the ribosome environment [19]. The lack of conformational change of clindamycin inside the mutant is probably due to its different binding mode and spatially smaller cavity in the mutated complex (Fig.…”

“…This O7–H12⋯O8 bond was present on average 34% of time, with the average O7–O8 distance of 2.74 ± 0.06 Å and O7–H12⋯O8 angle of 158.9 ± 3.1. As previously calculated, this hydrogen bond assures a lower energy conformer of clindamycin in vacuum and water environment [19]. However, in WT–CLY simulations, we also observed a change to a higher-energy conformer with respect to the dihedral angle C4-C7-N1-C10 (see previous sections), suggesting that there might be a connection between the internal O7–H12⋯O8 hydrogen bond in clindamycin and conformational change of its C4-C7-N1-C10 dihedral angle (Fig.…”

“…1). This happens because clindamycin can form an intramolecular hydrogen bond [19]. Indeed, Kostopoulou et al [25] using foot printing experiments and computational docking showed two clindamycin binding positions within the PTC.…”

“…In our previous work [19], at the B3LYP level of theory with the 6- 31G** basis set, we characterized clindamycin, lincomycin, and pirlimycin conformers both in vacuum and surrounded by point charges mimicking the electrostatic field of the ribosome. Combining the results of the natural bond orbital analysis and atoms in molecules theory, we described intramolecular hydrogen bonds in the above lincosamides.…”

“…Fortunately, structural data of some lincosamides and their targets are known. The structures of free lincosamides have been examined using experimental methods: X-ray techniques [ 16 , 17 ] and 13 C NMR spectroscopy [ 18 ], as well as computational techniques: quantum calculations [ 19 ] and molecular dynamics (MD) [ 18 , 20 ].…”