Summary
The halogenated 6-spiroepoxypenicillins are a series of novel semisyntheticβ-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potentβ-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retainβ-lactamase inhibitory activity.
Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains ofboth the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, ‘bioactive’ conformer for the classicalβ-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S2-subsite, specific for the side-chain aromatic moiety, and the 3α-carboxylate functionality is presented.
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This work has been reported in preliminary form at the 4th Royal Society of Chemistry International Symposium on Recent Advances in the Chemistry ofβ-lactam Antibiotics, Churchill College, Cambridge, U.K., 3–6 July 1988.
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Shute, R.E., Jackson, D.E. & Bycroft, B.W. Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin. J Computer-Aided Mol Des 3, 149–164 (1989). https://doi.org/10.1007/BF01557725
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DOI: https://doi.org/10.1007/BF01557725