Structure–activity relationships of the antiviral D4T and seven 4′-substituted derivatives using MP2 and DFT methods

• Published in: Structural chemistry 2013-06, Vol.24 (3), p.967-980
• Main Authors: Palafox, M. Alcolea, Iza, N.
• Format: Article
• Language: English
• Subjects: ATP; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Human immunodeficiency virus; Original Research; Physical Chemistry; Theoretical and Computational Chemistry
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-012-0193-x

A comprehensive quantum chemical investigation of the conformational landscapes of the anti-HIV D4T nucleoside analogue was carried out. Thus, all the possible stable structures were determined with full optimization of all the geometrical parameters. The whole conformational parameters ( χ , β , γ , P , ν max ) were analyzed. The hydration was simulated by explicit water molecules. The most stable conformer was determined as C1 either in isolated state as in aqueous solution, β  = 63.8°, N-type. Conformer C3 ( β  = 165.0º) is stable with 1–7 water molecules but with a number larger than eight, C1 is the only stable form in a close hydrated cluster. However, hydration of the natural nucleoside thymidine with 13 water molecules stabilizes the conformer C3 with β ca. 180º due to the presence of the C3′-OH group. The first phosphorylation step in D4T was simulated through the interaction with the ATP anion. This simulation was performed for C1 and C3 conformers in isolated state, showing that C1 changes to C3 by rotation of C5′-OH group until the value of β ca. 180º. Phosphorylation of hydrated clusters is only possible with a number of water molecules below of eight, which permits the C5′-OH group rotation to be accessible for the phosphate group. The bonding of D4TTP to DNA viral through the reverse transcriptase enzyme was also simulated. Seven 4′-substituted D4T derivatives were full optimized and analyzed on basis of the activity reported on TK-1 enzyme and effective concentration EC 50 , and several structure–activity relationships/tendencies were established. The two best correlations correspond to those observed between the TK-1 phosphorylation activity of D4T derivatives and AZT, and both the calculated exocyclic β angle and dipole moment.