Newsgroups: alt.drugs.chemistry
From: [e--u--s] at [netcom.com] (Eleusis)
Subject: Re: Revolutionary Method For Drug Design
Date: Wed, 8 Nov 1995 18:02:02 GMT

   [n--g--l] at [njosborn.demon.co.uk] (Nigel2) wrote:
>Here's an idea that I've been mulling over for some time, but haven't
>got the resources to develop further so I'm leaving it to anyone out
>there on the Internet to gain any glory from.
[snip]

This is quite interesting, and it's obvious that you've put a lot of work 
into it - I almost feel bad telling you it seems to have no chance of 
working at all.

Why? Because IgM won't cross the blood-brain-barrier. In fact, few of the 
immune cells, nor the globulins, can make it through. Practically any 
neuromodulation you would want to do for said purpose would require access 
to brain neurons - no access, no potentiation of drug effect.

Still, this is some of the best stuff I've seen posted here, theory-wise, 
in a long time.
--
      . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
     .        <[e--u--s] at [netcom.com]> - Finger me for my PGP Key          .
    .       _                                               _         .
   .       /o\    Give me lava lamps or give me death...   /o\       .
  .        \_/                                             \_/      .
 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


From: [n--g--l] at [njosborn.demon.co.uk] (Nigel2)
Newsgroups: alt.drugs.chemistry
Subject: Revolutionary Method For Drug Design
Date: Sun, 05 Nov 1995 20:01:52 GMT

Here's an idea that I've been mulling over for some time, but haven't
got the resources to develop further so I'm leaving it to anyone out
there on the Internet to gain any glory from.

It would appear to me that it should be possible to increase the
binding constant substantially for any drug acting against a surface
receptor, and possibly against an enzyme. This observation is based on
principles used by nature for many hundreds of millions of years but
curiously overlooked by science to date. 

   In the initial stages of the immune response the antibody class IgM
are produced clonal selection theory (which states that only those
plasma cells which bind to the immunogen are stimulated to proliferate
and produce antibody thus allowing the production of an antibody with
high avidity within a short time period). These basically consist of a
pentamer of dimer antibody molecules. The biochemical reason for
producing this rather oversized molecule is known to be the increase in
the binding of the antibody to the immunogen when the antibody has more
than one binding site. As IgM is produced early on in the immune
response it is not highly optimized for binding to the immunogen. By
producing a pentamer of dimers the binding is increased substantially
enough to keep the infection enough at bay to allow time for the
production of antibodies with higher avidity for the immunogen.
Similarly IgG antibodies, produced after IgM and consisting of  two
identical binding sites with a flexible hinge region are a model of
molecular design. For instance Stryer (p894 3rd eddition) estimates
that this dimer formation increases the binding constant by 104!

To understand the theoretical reason for this effect it is necessary to
understand the origin of the binding phenomenon. In any binding there
will always be factors which act for and detrimental binding. Thus
hydrophobic interaction, the hydrophobic effect, van der Waals
interactions, electrostatic interaction and p-p interactions favour
binding. However bad steric interactions, any changes of either species
away from their lowest energy conformation in solution on binding, loss
of rotational freedom of individual chains and loss of
translational/rotational momentum act against (D. H. Williams, J. P. L.
Cox, A. J. Doig, M. Gardner, U. Gerhard, P. T. Kaye, A. R. Lal, I. A.
Nicholls, C. J. Salter and R. C. Mitchell, J. Amer. Chem. Soc., 1991,
113). This latter factor is the effect that nature is using to its
advantage in the production of antibodies.  There are other
biomolecules that use this effect to their advantage. For instance the
Vancomycin group of antibiotics form dimers with themselves thus
increasing their potency.

Say if we have a drug candidate A binding to a receptor B. Each can
rotate and translate in the X,Y and Z plane before binding. After
binding both are forced to translate and rotate in unison thus a major
unfavourable entropic term is generated in the overall energetics of
the system.


By producing an antibody molecule with two binding sites the second
binding is enhanced. This is because the second binding site is much
restricted in both its rotational and translational freedom and thus
this particularly adverse component of the binding energetics is
reduced substantially. Obviously the factors which are positive to
binding are not affected in any way.

   The question that now comes to the fore is how we might use this
phenomenom in drug design. If we were to take a drug that acts on a
particular cell-surface receptor (X) with a particular binding
constant. We then form a dimer (or tetramer) of this drug-candiate,
obviously using any structure-activity relationships of the drug to
ensure that it does not sterically or electrostatically interfere with
the binding. I would expect to see at least a 103 increase in the
binding constant of the drug to the receptor.

   The next question that arises is how we might optimise the linker
component. Here the exact structure of the cell wall can be used to our
advantage. ICI have been using poly-guanisine polymers as
bacteriostatic agents for their paints. These work on the principle
that they disrupt the function of the plasma-membrane which is of
course identical in structure in eukaryotes by the positively charged
component binding electrostatically to the negatively charged phosphate
component exposed on the cell membrane surface.  By allowing the linker
component to be of this structure you could envisage that the drug
would be localized at the cell membrabe even before any interaction
occurs between the drug and the receptor.



I would personally expect that such a large molecule would not likely
gain passage to the cell membrane via an oral root though there are of
course vast numbers of incurable diseases which could be treated by
injection. The pharmaceutical market obviously doesn't develop non-oral
drugs for non-life threatening disease states.

Another biproduct of these ideas has implications for the synthesis of
agonsts vs antagonists. Present perceived wisdom on the subject
(M.S.Searle and D.H.Williams, J.Am.Chem.Soc., 1992, 114, 10690-10697)
indicates that antagonists are more likely to be compounds with good
enthalpic interactions with the receptor, whereas agonists tend to have
poor enthalpic interactions. The underlying reason for this appears to
be that greater enthalpic interactions means tighter binding to the
receptor thus causing a conformational switch inthe receptor. Thus by
increasing the binding constant we may be able to change an agonist
into an antagonist. Of course whether this is a desirable effect is
very dependent on whether this is desirable for the particular system
under study.

It is clear as with the design of any drug that the usual problems rear
their ugly head i.e. that of uptake in the intestine and p450
destruction.

An alternative design for such a drug might be to use a water-soluble
polymer to attach the drug such as the poly-lysine MAP developed by Tam
(ref?). Here we might have sixteen lysine amino groups available for
coupling to the drug. 

If anyone is interetsed in this idea then I'd be only to happy to guide
them in, hopefully, the right direction.

Nigel Osborn.