Subject: Binding of Flexible vs. Rigid ligands to a receptor

From: Viswanadhan <[email-masked]>
Date: Tue, 27 Feb 1996 15:10:03 +48000

Dear Netters:

I have a problem that is fairly typical in pharmaceutical drug design, 
but is not easy to solve. 

We have a fairly rigid cyclic molecule (C) which can exist in two 
conformations (puckers), C1 and C2.

Its acyclic analog (A) can also exist in different conformations, but
they are not separated by high barriers. C1 and some conformers of A
appear to have good interactions with a protein, but not C2.

In terms of binding geometry/energies C1 is better than A but A is 
much better than C2. C1 and C2 are separated by a high barrier, but 
they are isoenergetic (internal energy from QM calculations). 

TCP (free energy perturbation) calculations for the  mutation 
C1 -> A (or C2 -> A) will not reveal much because of the high barrier 
between C1 and C2 (making interconversion almost impossible in a 
reasonable time). 

Do you think it is possible to qualitatively assess the binding of C vs. 
A ?

Does it help to calculate the barrier C1 to C2, accurately? (via ab 
initio or MOPAC)? 

I will summarize your responses as well as my thoughts on the problem.

vis

[email-masked]