QSAR and molecular graphics analysis of N2-phenylguanines as inhibitors of herpes simplex virus thymidine kinases.
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.
Departamento de Física, Centro de Ciências Exatas, Universidade Federal do Espírito Santo, Vitória, Brazil. anderson@cce.ufes.br
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Gaudio
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WG
Richards
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Takahata
D000595:Amino Acid Sequence; D003196:Computer Graphics; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D018139:Simplexvirus / Q000201:enzymology*; D013223:Statistics as Topic; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D006147:Guanine; D013937:Thymidine Kinase