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Research Abstracts - 2006
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Molecular Design of Drug Resistance Resistant Inhibitors

David J. Huggins & Bruce Tidor

Introduction

AIDS is one of the major killers in the modern world, but despite the many treatments that have been developed, the HIV virus continues to spread. One of the main problems in designing drugs to combat HIV is the potential for the virus to develop resistance via mutation. This is a problem that affects drugs targeted at many organisms and is likely to become more of a problem with increased use of drugs to target viral and bacterial infection.

We have developed a strategy to help prevent this type of resistance by designing the drug molecule to mimic the exact shape of the substrates of the protein targets. The idea being that any mutations that affect drug binding will also affect substrate binding and thus have a deleterious effect on the organism. This is termed the substrate envelope hypothesis.

Methods

To aid in the synthetis of any compunds we design, a fixed scaffold is used as the basis for the inhibitors. We chose to target HIV protease for our inhibitors as it is a widely studied system and is considered to be one of the most effective targets to slow the spread of HIV. We have chosen to use the scaffolds of two of the most potent HIV inhibitors, Amprenavir and Lopinavir (See Figure 1 )

Figure 1

Figure 1 The scaffolds of amprenavir and lopinavir used for inhibitor design.
 

We then use a variety of commercially available compounds at the R1, R2 and R3 positions to design inhibitors with a high predicted binding affinity. However, the large number of scaffold positions combined with a large number of choices at each position and the necessity to search many conformations make this a complex problem. We use a combination of dead end elimination [1] and the A* algorithm [2] to analyse the many possibilities. This allows us to search a large portion of the space in a reasonable amount of time.

Current Progress

We have designed a series of compounds  from the lopinavir core based on the substrate envelope hypothesis. These compounds will shortly be tested for affinity and against a panel of mutants. The results will allow us to design a second set of compounds which are larger and predicted to bind more tightly but that do not mimic the substrate structure so well. These can then be similarly tested.

We have also been working with the synthetic chemists in an attempt to optimise some highly promising compounds based on the amprenavir scaffold. The marriage of experiment and theory will hopefully yield some highly promising inhibitors.

Future Plans

We hope to prove the concept of the substrate envelope hypothesis by designing and making molecules that mimic the shape of the peptide substrate of HIV protease and have good activity against a variety of mutant proteases. We can then establish a simple and effective methodology for to avoiding the problems associated with drug resistance in the future. This could greatly aid future efforts in drug discovery.

References:

[1] J. Desmet, M. De Maeyer, B. Hazes and I. Lasters. The dead-end elimination theorem and its use in protein side-chain positioning. Nature 356, p539542, 1992.

[2] A. R. Leach and A. P. Lemon. Exploring the conformational space of protein side chains using dead-end elimination and the A* algorithm. Proteins 33, p227239, 1998.

 

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