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Prediction of bond length variation in classical β‐lactam structures and enzymatic ring instability
Author(s) -
Scanlan M. J.,
Hillier I. H.,
Hodgkin E. E.,
Sidebotham R. P.,
Warwick C. M.,
Davies R. H.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560240724
Subject(s) - lactam , chemistry , ring (chemistry) , instability , bond length , substituent , computational chemistry , stereochemistry , ring size , crystallography , crystal structure , organic chemistry , physics , mechanics
Comparison of intrinsic, solvational, and enzymatic rates of β‐lactam ring opening allows rate enhancement due to specific enzyme interactions with given β‐lactam moieties to be identified and modeled. Enzymatic rates of β‐lactam ring opening may be derived from potency data and are briefly reviewed. For widespread comparison with intrinsic instabilities, convenient criteria for accurate estimation of the latter are required. The conditions under which differences in intrinsic instabilities of β‐lactams correlate closely with their ground‐state properties have been defined. Theoretical prediction of substituent effects in β‐lactam structures requires geometry optimization if accuracy with the biological instability data over even moderate ranges of activity is to be maintained. The β‐lactam amidic C‐N bond length is a powerful indicator of intrinsic ring instability. The contributions of the ring nuclei to enzymatic stability in classical β‐lactam structures correlate with the predicted C‐N bond lengths for both STO‐3 G and 4‐31 G bases to ˜0.4 kcal. This accuracy corresponds to a bond length sensitivity of ± 0.004 Å. The limits of convergence of the theoretical estimates are of this order. The relative theoretical amidic C‐N bond lengths offer a more precise scale for ranking intrinsic β‐lactam instabilities than one employing experimental X‐ray quantities, with their associated perturbations from crystal forces. A specific interaction of 6/7 acylamino substituents in penicillins and cephalosporins with pbp I enzymes is identified.