ABSTRACT
A quantitative structure-activity relationship study of N2-(substituted)-phenylguanines (PHG) as inhibitors of herpes simplex virus thymidine kinase (HSV TK) was performed. The activity of a set of PHG derivatives were analyzed against the thymidine kinase of herpes simplex virus types 1 (HSV1 TK) and 2 (HSV2 TK). Classic and calculated physicochemical parameters were included in the analysis. The results showed that there is an important difference in the activity of the meta substituted PHG derivatives against HSV1 TK and HSV2 TK. The activity of the meta derivatives against HSV2 TK is influenced by a steric effect, which is not observed against HSV1 TK. The superposition of the three-dimensional structures of the active sites of HSV1 TK (crystal structure) and HSV2 TK (homology model) revealed that the amino acid Ile97 is located near the meta position in the HSV1 TK active site, whereas the amino acid Leu97 is located near the meta position in the HSV2 TK active site. This single difference in the active sites of both enzymes can explain the source of the steric effect and serves as an indication that our previously proposed binding mode for the PHG derivatives is plausible. However, another observed mutation in the active site region, Ala168 by Ser168, suggests that an alternative binding mode, similar to that of ganciclovir, could be possible.
Subject(s)
Computer Graphics , Enzyme Inhibitors/chemistry , Guanine/analogs & derivatives , Guanine/chemistry , Simplexvirus/enzymology , Thymidine Kinase/antagonists & inhibitors , Amino Acid Sequence , Computer Simulation , Enzyme Inhibitors/pharmacology , Guanine/pharmacology , Herpesvirus 1, Human/enzymology , Herpesvirus 2, Human/enzymology , Models, Molecular , Molecular Sequence Data , Molecular Structure , Quantitative Structure-Activity Relationship , Sequence Alignment , Statistics as Topic , Thymidine Kinase/chemistry , Thymidine Kinase/metabolismABSTRACT
The probable binding mode of the herpes simplex virus thymidine kinase (HSV1 TK) N2-[substituted]-phenylguanine inhibitors is proposed. A computational experiment was designed to check some qualitative binding parameters and to calculate the interaction binding energies of alternative binding modes of N2-phenylguanines. The known binding modes of the HSV1 TK natural substrate deoxythymidine and one of its competitive inhibitors ganciclovir were used as templates. Both the qualitative and quantitative parts of the computational experiment indicated that the N2-phenylguanine derivatives bind to the HSV1 TK active site in the deoxythymidine-like binding mode. An experimental observation that N2-phenylguanosine derivatives are not phosphorylated during the interaction with the HSV1 TK gives support to the proposed binding mode.
Subject(s)
Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Guanine/analogs & derivatives , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/enzymology , Thymidine Kinase/antagonists & inhibitors , Thymidine Kinase/metabolism , Amino Acid Sequence , Antiviral Agents/chemistry , Binding Sites , Binding, Competitive , Computer Simulation , Enzyme Inhibitors/chemistry , Ganciclovir/chemistry , Ganciclovir/metabolism , Ganciclovir/pharmacology , Guanine/chemistry , Guanine/metabolism , Guanine/pharmacology , Humans , Models, Molecular , Phosphorylation , Protein Conformation , Sequence Homology, Amino Acid , Species Specificity , Thermodynamics , Thymidine/chemistry , Thymidine/metabolism , Thymidine Kinase/chemistryABSTRACT
A quantum chemical (AM1) combined with a classical study of structure-activity relationships for 1,4-dihydropyridines (nifedipine analogues) was performed. The biological data were taken from the literature. The quantum chemical parameters tested were energies of HOMO and LUMO, dipole moment (total and partial), hardness, Mulliken electronegativity, frontier orbital indices, and others. Also tested were classical parameters like Hansch hydrophobic constant, tau; Hammett electronic constant for the meta position, sigma m; and the Verloop sterimol parameters, B1 and L. The van der Waals volume was also tested. The pharmacological activities of the para monoderivatives are negatively correlated with the molecular volume, i.e. a steric factor. The meta position of the phenyl ring is affected by steric and electronic parameters, whereas the ortho position seems to be affected by hydrophobic and electronic parameters.