Quantum Chemical and Molecular Mechanics Studies on the Binding of Stereoisomers of the Oligopeptide Antibiotics Amidinomycin and Noformycin to the Minor Groove of B-DNA

Abstract

Ab initio calculations (Hartree-Fock) using the 6-31G basis set have been performed on two chiral oligopeptide antitumor antibiotics amidinomycin 5 and noformycin 6. The latter are DNA minor groove binding agents related to the A.T recognizing netropsin 4 and distamycin 3 but, unlike the latter, bear stereocenters (two for 5 and one for 6) that may be expected to affect binding to the B-DNA receptor. Geometry optimized conformations, energies and distribution of electrostatic charges within the molecules were derived. The rotational barrier for bond C3-C6 in 6 was calculated to be ca. 6 kcal.mole-1 and the dipole moment for 6 was 7.69D and for 5 was 5.58D. The ab initio derived parameters of the geometry optimized conformations of the different possible stereoisomeric forms of 5 and 6 were used to interpret their different interactions with the minor groove of DNA at both A.T and G.C sequences and the results were compared with molecular mechanics calculations. The order of binding of the four stereoisomers of 5 at the preferred (A.T)n sequences by both ab initio and molecular mechanics calculations is 1S,3R > RR > RS > SS. The predicted energy differences for complexation with DNA of the other stereoisomers from that of 1S,3R are: RR (4.2%); RS (6.7%) and SS (21.5%). In the case of noformycin the 4R structure binds more effectively than the enantiomer. Considerations of phasing in the computed distances between hydrogen bond donating sites in the DNA-bound antibiotics provide further insight into the binding processes. In the complexes of noformycin 6 the N-N1-N4 and N1-N5 distances (9.05 and 9.15 A respectively for 4R-6 and 9.23 and 9.26 A respectively for 4S-6) are close to the optimum value of 9.1 A for effective binding. In the case of amidinomycin 5 the best agreement with the optimum value occurs with the strongest binding diastereomer 1S,3R (N1-N3 = 8.91, N1-N4 = 9.41 A). The unexpected result, consistent in both ab initio and molecular mechanics treatments, is that, in contrast to the cases of kikumycin 1 and anthelvencin 2, the natural 3S configuration of 5 and 4S of 6 do not confer maximal binding efficiency. This suggests that biogenetic factors in the generation of the oligopeptide antibiotics lead to maximum DNA binding in the cases of kikumycin and anthelvencin but not in the cases of amidinomycin and noformycin.

Naturally Occurring Proline Analogues

“…The antibiotics termed kikumycins A ( 5 ) and B ( 6 ) − (from Streptomyces phaeochromogenes) , noformicin ( 7 ) (from Nocardia formica ), and anthelvencin A ( 8 ) , (from Streptomyces venezuelae ) have also been represented as having structures with the tautomeric 5-iminoprolyl moiety. These compounds have antimicrobial, and also antiviral activity, especially noformicin. , Their biological activity is exerted through binding to the minor groove of DNA. ,

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“…82 The lincomycins have been reviewed. 83 (22) of unreported streochemistry is a component of the peptide lactone antibiotic hormaomycin (from Streptomyces griseoflavus), which is active against some Grampositive bacteria, especially Arthrobacter species. 84,85 It has potent aerial mycelium-inducing activity.…”

Quantum Chemical Studies Employing anAb InitioCombination Approach on the Binding of the Bis-Benzimidazole Hoechst 33258 to the Minor Groove of DNA

“…We reported the application and utility of this approach to prototype lexitropsins (21). Certain chiral oligopeptide antibiotics, due to their smaller size were subjected to the complete optimization of the entire molecule (22). The present study concerns the application of this method to Hoechst 33258, the prototype benzimidazole 1.…”