QSAR of phenylguanine analogues of HSV-1 Thymidine Kinase Inhibitors

Abstract

Introduction

Incidence of disease Need for novel therapies How to achieve this using QSAR

Herpes simplex virus is a member of the alpha herpes virus family that are nuclear DNA viruses (Williams and Lemke, 2002). It is widely distributed in humans, HSV type 1 (HSV-1) usually affects the upper parts of the body such as; eyes, mouth and brain (Gaudio and Richards, 2000). Thymidine Kinase which is induced by HSV-1 is significant in antiviral activity of phenylguanine derivatives such as acyclovir, which significantly reduces DNA synthesis in virus infected cells without disturbing the active replication in infected cells. As stated by Williams and Lemke, 2002 acyclovir is a synthetic analogue of deoxyguansine, its mode of action consists of the conversion to active acyclovir monophosphate within cells by viral thymidine kinase, thus inhibiting it, acyclovir can then further be converted to di- and triphosphates by a normal cellular enzyme called guanosine monophosphate kinase. These triphosphates are incorporated into the viral DNA chain during DNA synthesis, thus terminating further elongation of the DNA chain due to lack of 3’- hydroxyl group of a cyclic sugar.

Gaudio and Richards 2000 analysed a series of meta substituted phenyl guanine analogues for inhibitory activity against HSV-1 thymidine kinase and found that there are 16 phenylguanine analogues which only differs at position X (Figure 1). Thus using this information I will attempt to identify the molecular properties of the chemical groups at position X that are important in determining the inhibitory activity of the phenylguanine. As well as deriving quantative models and an equation that can be used for the rational design of HSV-1 thymidine kinase inhibitors.

Method

QSAR was analysed using the HSV-1 Raw file which contained the parameter data with its inhibitory activity for the phenylguanine analogues. Parameters tested in this analysis were substituent hydrophobicity constant (Pi) and Hammet substituent constant (Sigma). Using this information the HSV-1 correlation was obtained which aided in deciding on the two parameters chosen. Moreover a HSV-1 regression analysis was obtained which contained coefficients which identified the values to use in deriving an equation, as well as giving an insight to the quality of this model. Furthermore the effectiveness of the model at predicting HSV-1 activity was

evaluated by predicting the activities of the four phenylguanine analogues excluded from test set. Finally using OtherSubs worksheet, active analogues which should be synthesised were predicted.

Discussion

References