[Jack17]

Hey guys!

I'm doing some reading on quantum chemistry and wondered if somebody could help me with this question:
Would knowing the quantum chemical electronic structure of a molecule allow us to predict and design other molecules that will interact / bind with it?
I'd really appreciate any help on this! Thanks for your time!

Best wishes,
Punita

[acmars]

quantum chemical only could predict and design other simple or stable molecules.

[lemonoman]

If only we knew that much about quantum chemistry

In reality, approximations to reality are used to predict stuff like that.  There are computer programs out there to help us predict what will react/bind to what.

I've used Gaussian to predict binding of molecules in the gas phase.

A friend of mine has used Sybil to design inhibitors for certain enzymes.

Most of the calculations are based on electronic structure, but we are very far away from being able to do it without making approximations.

[Jack17]

Hey acmars and Lemonoman!

Thanks so much for getting back to me! Your comments were really useful!
  Could I ask whether you think in the future 'rational design' of materials (for example, building a ligand 'into' a known receptor to bind with it) will be possible when we have a deeper understanding of quantum chemistry? Or is rational design always going to be a problem of searching the vast chemical space to find a 'match'? 
  I know many people still categorise the latter as being 'rational', but it seems to me if we even if we somehow searched a chemical space of as many as 10^20 chemicals, we've covered much less than one per cent of the possible chemical  space! 
  Do you think quantum chemistry will (in the future) solve that problem of an almost infinite search space for us by enabling us to design the required ligands directly using the knowledge of the receptor's quantum structure? 
  Thanks again for getting back to me on this and helping me!
Best wishes, Punita

[lemonoman]

Maybe it's because I'm only a B.Sc., but I don't understand your question at all.

Do you mean, binding enzymes to surfaces, so that you can have surface reactions that way?

There are an infinite number of molecules that can be formed, because molecules can just get bigger and bigger.  There is no finite 'chemical space', in terms of what I think you're saying.

Reply back, we'll talk

[Yggdrasil]

Some work has been done designing enzymes and proteins which bind to certain ligands.  Here, the approach people normally take is classical (obviously, proteins are too large to treat quantum mechanically).  Researchers have developed force fields describing intermolecular interactions and they apply these force fields to design and optimize interactions between proteins and ligands.

Two researchers who do this kind of work that I can think of off the top of my head are Homme Hellinga at Duke University and David Baker at the University of Washington.

[Jack17]

Hey guys,

Sorry for the delay in getting back; a close friend went into labour during the week so I didn't have much free time.
 Yggdrasil - thanks for your reply. Out of interest do you know how accurate any of those force fields are?
 Lemonoman - thanks for getting back. Sorry if I didn't make clear what I was saying.  I understand the chemical space is infinite, and that's why I'm wondering how easy chemists find it to know what particular structures will bind to (for example) an enzyme. (By the way, when you say you're 'only' an B.Sc, that kind of scares me! I'm still a first year college student, so please bear with me!)
  Maybe I can offer an example of what I'm getting at.  A friend of mine was recently involved in designing a virtual screening software package which I think she said screened about  10^5 molecules a year against an enzyme to find an 'optimal' bind to use as a basis for a ligand.  But I don't understand the point in screening 10^5 molecules, because the amount of chemicals possible is infinite.  I think many medicinal chemists put the number (roughly) somewhere between 10^60 to 10^400 for chemicals useful to them - of which only I think about 10^10 or so have ever been made. These numbers are clearly all crazy.  But as a very rough guide, 10^5 molecules is hardly anything (as a percentage of 10^60 is pretty much doesn't even register). 
  So can I ask you a question: say I came to you in your lab and said, 'hey I have an enzyme with it's electronic structure (or even just molecular structure), and I need you to make me a chemical to bind with it / part of it so as to alter its function in a desired way' - could you do that?  Or is that really difficult to do?  And if it is, then how do chemists 'rationalise' the way they go about creating new ligands?
  One other question (if I may?): have you ever used Sprout or Ludi in their de novo forms?  I heard they have some problems with applicability - do you have any thoughts on this?
  Thanks again for your time!  I really appreciate your help in this!
Best wishes, Punita

[Borek]

You don't have to screen every possible molecule, some can be easily rejected without hesitation. When you have runny nose you look for a soft tissue, you will not try hammer, wall paint, mobile phone or book. That's more or less what chemists do - after all, they have experience in dealing with molecules

[Yggdrasil]

The basic problem of designing ligands to bind enzymes is one that the pharmaceutical industry works on every day.  I've seen a few general approaches that might be looking into:

1) Rational design.  Basically, if you want to find an inhibitor of an enzyme, a good way to start is to modify the enzyme's substrate to try to find a related compound which will block the activity of the enzyme.  This is the most traditional approach.

2) Chemical genomics.  You have a library of a huge number of compounds and a cell-based assay to determine whether the compound inhibits your enzyme of interest.  This will allow you to screen a large portion of chemical space, although not all the hits from the screen will likely bind with high affinity.

3)  Peptide/aptamer evolution.  Through something like a phage display library, one can design a method to evolve a small amino acid sequence or nucleotide sequence to bind to an enzyme with high affinity.  This approach is problematic, though because peptides and aptamers aren't really effective as drugs since they are rapidly degraded by the body.

Another interesting technique I've come across is SAR by NMR, made by Stephen Fesik.  Here's the pubmed reference:

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=8929414&dopt=Abstract

As for the force-field methods, I don't know too much about the topic so I can't really comment on how well they work.  People have had success predicting simple protein structures with force field methods and designing novel protein-ligand interactions, but the method is far from perfect.

[lemonoman]

Kickass reply, Yggdrasil

Number 1 (Rational Design) is my favorite, because it puts a little bit of art in science.  You can bring up the chemical structure of the enzyme on a computer, 'invent' a molecule to inhibit/modify it, then once you think you have a good molecule, you get to try to synthesize it.  It's like solving a different puzzle each time

[Yggdrasil]

Rational design methods v. directed evolution methods (e.g. chemical genomics or peptide evolution), to me, represents the difference between chemists and biologists.  Chemists will do rational design because they prefer working from first principles to find a "elegant" solution to a problem.  Biologists, on the other hand, often don't work from first principles (often because these principles are unknown or too complex to work with), so they prefer designing high-throughput assays to search a huge amount of chemical space and find an inhibitor through brute force.

[Jack17]

Hey guys! Thanks for your help, that was really helpful!

Many kind regards!