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.