Complete conformational space of the potential HIV-1 reverse transcriptase inhibitors d4U and d4C. A quantum chemical study

Abstract

A comprehensive quantum-chemical conformational analysis of two nucleoside analogues, 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-didehydro-2',3'-dideoxycytidine (d4C), is reported. The electronic structure calculations were performed at the MP2/6-311++G(d,p)//B3LYP/6-31++G(d,p) level of theory. It was found that d4U and d4C adopt 20 conformers and 19 conformers, respectively, which correspond to local minima on the respective potential energy landscapes. QTAIM and NBO analyses show that the d4U and d4C conformers are stabilised by a complicated network of specific intramolecular interactions, which includes conventional (OHO) and non-conventional (CHO, CHHC) H-bonds as well as closed-shell van der Waals (CO) contacts. A satisfactory linear correlation was found between Grunenberg's compliance constants for closed-shell intramolecular interactions and their energy. It is shown that there are no conformational obstacles for incorporation of d4U and d4C into the double helical A and B forms of DNA. The less pronounced biological activity of d4U as compared to 2',3'-didehydro-2',3'-dideoxythymidine (d4T) is most likely due to the presence of the bulky methyl group at the 5-position of d4T, which can be recognised by target enzymes.

Enhanced Aerogen–π Interaction by a Cation–π Force

“…[14,16] Our results show that the relaxed-force constants are quite small (i.e., < 0.100 mDyn À1 )f or most of the Xe···C noncovalent interactions, especiallyf or complexes containing am onovalent cation. [14] Consistent with the interaction energy,t he f R value of the divalent cation complex is greater than that of am onovalentc ation. [14] Consistent with the interaction energy,t he f R value of the divalent cation complex is greater than that of am onovalentc ation.…”

“…All of the cations adopted are essential elements for the human body,i ncluding the Li + ,N a + ,K + ,C u + ,M g 2 + , Ca 2 + ,Z n 2 + ,N i 2 + ,a nd Fe 2 + ions. [14] There are two important geometrical parameters that characterize this strong interaction, one is the closer contact between the Zn 2 + ion and the center of the benzene ring, the other is the distance of the xenon atom from the center of the benzene ring, which is the shortest distance among the complexes studied.T he Ni 2 + -C 6 H 6 ,Fe 2 + -C 6 H 6 ,and Mg 2 + -C 6 H 6 systems share aclose resemblance to the Zn 2 + -C 6 H 6 system in its energetic and structural features. Our results show that divalent cation-p systems bind the xenon atom quite intensively,e specially the Zn 2 + -p and Ni 2 + -p systems.…”

Behavior of Halogen Bonds of the Y−X⋅⋅⋅π Type (X, Y=F, Cl, Br, I) in the Benzene π System, Elucidated by Using a Quantum Theory of Atoms in Molecules Dual‐Functional Analysis

“…Very recently, the nature of the triple bonds between boron atoms was clarified based on such relaxed force constants . A comprehensive quantum‐chemical conformational analysis was performed on nucleoside analogues, in which the role of intramolecular closed‐shell interactions was elucidated by using the compliance force constants in addition to QTAIM and NBO treatments …”

Benchmark calculations of intramolecular hydrogen bond energy based on molecular tailoring and function‐based approaches: Developing hybrid approach

“…The usefulness of additional quantum‐chemical calculations with B3LYP/6‐311++G(d,p) protocol follows from the fact that the B3LYP is one of the most popular functional and it is used in conjunction with the Pople basis most often in the study of hydrogen bonds . Besides, the calculations performed at the DFT level expand the base of equations, through which one can evaluate the energy of the hydrogen bond.…”