On Tue, 6 Jun 2000, Petr Kuzmic wrote:
> The issue often was the
> interpretation of the Michaelis constant by people interested in
> designing inhibitor drugs as substrate analogs (or as transition state
> analogs, which is another soap-box issue in an of itself). Of course,
> if and only if the chemical step is perfectly "rate limiting" (Rapid
> Equilibrium Approximation), then I suppose the Michaelis constant could
> be interpreted as a thermodynamic equilibrium constant. Some people
> were then looking at small peptide substrates for proteases, trying to
> select those with low Km and chemically modify them into successful
> inhibitor drugs. And failing, of course.
I assume you were specifically thinking of HIV-1 protease, is that correct
Petr? Do you feel the reason for the spectacular failure lay in the
methods by which people arrived at their optimised inhibitor? Too often
people tried to functionalise from left to right, then threw their arms in
the air when co-operative effects influenced the binding to such an extent
they could no longer tell why their inhibitor failed.
To reflect now at the lack of rational design over combinatorial chemistry
(incidentally combi chem is starting to be called rational drug design
now, it's only rational to a chemist though), I believe it is fair to say
the boat has been missed by most people because no rules for substrate
recognition have been fully tested. I believe the work outlined by
Henderson et al (Henderson et al., (1988) "Molecular Characterization of
gag Proteins from Simian Immunodeficiency Virus (SIVmne)" J. Virol
62; 2587-2595) was a brilliant start point that should never have been
rejected. Others go on (or form their own opinion - Methods in Enzymology
(1994)), but nothing comes close to the Henderson rules.
Indeed, following these rules you can make a *very* potent
inhibitor. Perhaps now in light of viral resistance we can return to real
drug design. Which brings me to a question - why do you think it is that
assays for HIV-1 PR/inhibitors conducted with mutant enzymes and the
compounds that select them fail to predict the said selection?
Len...
