An investigation of the conformation of peptide-T and its D-Ala analog by NMR and molecular dynamics simulations.

Peptide-T (ASTTTNYT) and its D-Ala analog (D-ASTTTNYT-NH2) have been designed to block the adsorption of HIV to CD4 receptors on T-cell lymphocytes, thus inhibiting viral infectivity. The conformation of these important peptides has been investigated by 2D-NMR and molecular dynamics simulations. The NMR studies in DMSO show that the peptides exist in solution as a mixture of conformations. beta-Turns and non-specific folded conformations are present in a small proportion in the ensemble of conformations, which is largely dominated by more or less extended structures. This result is in line with molecular dynamics simulations where beta-turns were found to occur with a low frequency and with energies 10 to 17 kcal/mole higher than the global minimum structure. Our findings differ from previous reports on the conformation of peptide-T determined by NMR.

Conformation of azidothymidine: an anti-AIDS drug.

The nucleoside antibiotic, 3'-azido-3'-deoxythymidine, or simply, azidothymidine has shown great promise in inhibiting the human immuno deficiency virus and in reducing mortality among AIDS patients. Conformational properties of azidothymidine have been investigated by quantum-mechanical PCILO method and compared with those of the parent nucleoside, thymidine. The results indicate great similarity between them and this similarity is remarkably striking in the situations that prevail in aqueous solution. This result has important biological significance in explaining the drug action of azidothymidine.

Biological activity of an antibiotic puromycin—A theoretical study.

Puromycin is known to be an anti-tumor agent. Evaluation of interaction energy of this molecule with nucleic acid bases and base pairs has been performed using quantum-mechanical perturbation technique. Both in-plane and stacking energies have been evaluated. These energy values along with their sites of association have been compared with the standard values during transcription process. The results have been examined in the light of their biological significance.

Amsacrine binds in a cooperative manner to deoxyribonucleic acid.

The intercalative binding of the acridine antitumour drug 4'-(9-acridinylamino) methane-sulphonate-m-anisidine, a known inhibitor of nucleic acid synthesis, to native calf thymus DNA has been studied using optical titration method. Amsacrine (AMSA) exhibits positive cooperativity in their equilibrium binding to DNA as indicated by the positive slope in the initial region of the binding isotherms (Scatchard plots) under conditions simulating physiological ionic strengths. m-AMSA binds with a higher degree of cooperativity than o-AMSA. Although this correlates with the effectiveness of the drugs as antitumour agents, the exact relationship between the observation of cooperative binding and pharmacological activity is yet to be determined.

Mode of action of intercalators: a theoretical study.

Mode of action of some intercalators has been theoretically investigated on the basis of quantum mechanical perturbation method. Energies of H-bond interaction between drug chromophore and base pairs have been calculated in all possible orientations. The stacking energy has also been calculated with the base pairs. The effect of these interactions on specific recognition has also been discussed. On the basis of these studies, a model for the interaction of these drugs has been proposed. This explains the relative activities of acridine intercalators and satisfies the experimental observations.