Molecular simulation of 5,6-substituted 1-[(2-hydroxyethoxy)methyl]uracils with anti-HIV-1 activity

Comparative Quantitative Structure−Activity Relationship Studies on Anti-HIV Drugs

“…Although many physicochemical properties of non-nucleoside RT inhibitors can differ, many theoretical studies seem to establish that these inhibitors possess a common three-dimensional feature which has a rigid butterfly-like configuration that fits well into a sizable internal cavity of the allosteric area of the enzyme. − A large, highly hydrophilic and constrained Ω-loop (Figure ) was dissected from the allosteric area of HIV-1 RT (segment Tyr181− Tyr188). , The loop contains two amino acids (Asp185 and Asp186) of catalytic aspartyl triad and two amino acids (Tyr181 and Tyr188) of NNRTI binding sites and is stabilized by the hydrogen bonding between CO of Tyr181 and the peptide NH of Tyr188. A butterfly-like configuration of an NNRTI (say nevirapine) can be represented as shown in Figure .…”

A check on rational drug design: Molecular simulation of the allosteric inhibition of HIV-1 reverse transcriptase

“…However, a common butterfly-like shape was hypothesized for TIBO, ␣-APA, (phenylthio)thymines, nevirapine, and dihydrothiazolisoindolone. [42][43][44][45] It will now be shown that this hypothesis can be generalized and that a quantitative evidence 41,45 is possible. It should be added that such a configuration is not unknown in medicinal chemistry.…”

“…18, Table X) were taken from the literature. 45 The following descriptors were of interest: With respect to R 1 substituents, the position-dependent (ortho, meta, para) lipophilic substituent constant N Ϫ (octanol/water), the hydrogen-bonding parameter pK H derived from the equilibrium constant of hydrogen bonding between substituted benzenes and phenol as hydrogen donor (in CCl 4 , at 25 ЊC), and the scaled molar refractivity MR. Furthermore, the STERIMOL parameters L (length) and B1 (minimum width) were determined.…”