drugs and electrons
DESCRIPTION
A talk to Paul W. Ayers' group at McMaster University in Hamilton, ONTRANSCRIPT
Drugs and Electrons
David C. ThompsonMarch 2008
Overview
A little bit about why we make drugs, andhow computational chemistry is used (myday job)
A little bit about confined electronicsystems, informational entropy, andcomplexity (my evening job)
A novel 3D QM based structural descriptor(my afternoon job?)
Drugs - why do we make them?
1. Money 2. And I guess you can help people too3. But mainly for the money
Drugs - how do we make them?
From a computational perspective I willlimit myself to Structure-Based DrugDesign (SBDD)
Drugs - how do we make them? What are we trying to do?
In SBDD we use computational chemistry to capture somepart of this incredibly complex interaction by modeling theprotein-ligand binding event
We typically ‘ignore’: Protein flexibility, polarization and other electronic factors,
solvent, entropy . . .
+ = ?
And what have I been doing? Detailed analysis of the in-house high-throughput virtual
screening protocol Accepted in J. Chem. Inf. Mod.
Fragment-based de novo design CONFIRM Submitted to J. Comput.-Aided Mol. Design
A large scale critical assessment of docking programs Binding mode prediction Enrichment rates in virtual screening Method development: Docking pose assessment tool
The Hospital that ate my Wife
Given the tools of our trade:
I can still work on problems in electronic structure Information theoretic properties of strongly
correlated systems Prof. Kalidas D. Sen, University of Hyderabad Dr. Ali Alavi, University of Cambridge
Electrons and how they get along
PhD in small model quantum systems Particles-in-a-box Exact solutions
Archetypal systems for investigating electroncorrelation
Electron correlation arises as a consequence of thesimultaneous interactions of mutually repellingparticles It is what makes QM a ‘tricky’ problem both
conceptually, and practically
Basic physics of these systems
Two regions of behaviour Small R - kinetic dominance Large R - Coulombic dominance
E ~ A/R2 + B/R + …
Wigner ‘crystal’ formation at large R
Properties of interest( )
( )
( )
( )( )
( ) ( )
( ) !
!
!
"=
#=
"=
"=
"
N2
2
1
2xc
N321
2
2
N21
2
1
N1ii
xd...xd||N'x,x
'rn'r,rnrn
2'r,rn
xd...xddsds||2
1)-N(N'r,rn
xd...xdds||Nrn
x...x , E
rrrr
rrrr
rr
rrrr
rrr
rr
$
Density:
Second orderdensity matrix:
Physicalexchange-correlationhole:First orderdensity matrix:
Eigenvalues andeigenvectors:
FCI, RHF, UHF, and LDA solutions for both the spherical(N=2, 3, 4, and 5) and cubic/planar (N=3, and 4) geometries
Spherical two electron system
Spherical two electron system
RHF solution is surprisingly simple (S=0)
And rapidly convergent for even large R(µmax=7)!
"(r) =1
4#Cµ j0µ=1
µmax
$ (%µ0r)
Spherical two electron system:RHF and informational entropy
!
Sr = " #(r)$ ln[#(r)]dr
Sp = " %(p)$ ln[%(p)]dp
ST = Sr + Sp
Spherical two electron system:Complexity - RHF
Spherical two electron system:Complexity - Hylleraas
A novel descriptor? Doesn’t Sr look a little familiar? Continuous form of a measure used in molecular
similarity:
Could we use Sr as a measure of similarity? Moreover, could Sr be a 3D QM-based structural
descriptor? Literature search has shown that this has not been
considered before (I think)!
S = " pii
# ln[pi]
A novel descriptor?
We want to make this useful But we still have the problem of finding ρ in a timely fashion
Why don’t we approximate ρ? We construct a pro-molecular density from a sum of fitted s-
Gaussians
Turns out that this isn’t as bad as you might think
!
"(r) # "Mol(r) = "$ (r)
$
% = c$ii
% exp(&'$i(r &R$ )2)
$
%
Homebrew quantum mechanics
All of this has been done on my iMac at home
Molecular integrations performed using theBecke/Lebedev grids in PyQuante[1]
Co-opted James into doing MathCad checks forme. . .
[1] Python Quantum Chemistry - http://pyquante.sourceforge.net/
Homebrew quantum mechanics
RzH1 H2
Homebrew quantum mechanics
-35.94Cyclohexane (chair)
-27.09Benzene
3.94H2S
-7.42H2O
SrMolecule
Perhaps Sr isn’t that discriminatory?Plan B -
!
Sr(r) = "#(r)ln[#(r)]
And that might look like. . .
Conclusions and outlook
Hopefully you have a feel for what I have beenworking on, and why it might be interesting/useful
Work with Prof. Sen is being written up Extend to planes - see if signature holds for N>2
At BI incorporate descriptor into a QSAR model Is it of any use at all - what about Sp?
Acknowledgments
Wyeth Research Prof. Sen and Dr. Alavi You all