Subject: Summary: Rigid receptor models

From: "Simon Kilvington" <[email-masked]>
Date: Fri, 19 Apr 1996 13:21:41 +0100 (BST)

Here is my original query:

        does anyone know where I can find a good discusion about the use
of rigid vs flexible receptor models in computer-aided drug design?

Most of the replies I got were from people asking for summaries.

There are not many discussions on this topic, but you may want to look
at... 

W.L.Jorgensen, Science 254 (1991) 954-955.
"Rusting of the lock and key model for protein-ligand binding"

- this talks mainly about ligand conformation changes on binding.

A.Weichsel, W.R.Montfort, Nature Structural Biology 2 (1995) 1095-1101.
"Ligand-induced distortion of an active site in thymidylate synthase upon
binding anticancer drug 184U89"

- I'm still waiting for this to arrive via the inter library loan system
so I can't comment on it yet.

P.Groontenhuis, P.van Galen, Acta Cryst. D51 (1995) 560-566.
"Correlation of binding affinities with non-bonded interaction energies of
thrombin-inhibitor complexes"

- a QSAR binding prediction paper with some discussion about receptor
rigidity. It also references a talk Scot Dixon gave at a conference in
1994 about host conformations not changing too much on ligand binding.

And there is some work by Martin Karplus on protein dynamics, eg

R.Elber, M.Karplus, Science 235 (1987) 318-321.
"Multiple conformational states of proteins: a molecular dynamics analysis
of myoglobin"

After looking at all these and some general biochemistry text books (eg
Stryer), here's a very brief summary of what I've put in my thesis... 

there's not much doubt that proteins are rather flexible systems.
  
or that some undergo conformational changes on ligand binding.

but they achieve their prodigious catalytic abilities by binding their
substrates in conformations that distort the substrate geometry towards
the transition state of the reaction.

so as inhibitors that bind the active site generally work by mimicing
the transition states of substrates while being unable to be catalysed,
we are justified to a certain extent in using a rigid model of the
receptor - as long as it is in a conformation that causes the substrate
to adopt a transition state geometry. 

If anyone has any ideas/comments about this argument I'd be very glad to
hear them.

---
Simon Kilvington, [email-masked]