Knowledge Based Reactions

Outside of quantum mechanical modeling, typical method is to explicitly specify the participating reactant atoms and how bonds are rearranged as a reaction profile

R1

O

OH

NH2-R2

H+

Sample Reaction Profile

R1

O

+ H2O

NH2-R2

Knowledge Based Limitations

Requires manual pre-specification of many different known reaction profiles to achieve any degree of generalization

+ +

+ +

+

Knowledge Based Limitations

A very generic reaction profile can cover everything from previous slide and indeed about 50% of all known organic reactions

Still, a screening or ranking method is needed to filter many unrealistic reactions proposed above

Many reactions with more sophisticated profiles are not covered without manually specifying more knowledge based profiles Diels-Alder Azide + Alkyne aromatic cyclization

A B

C D

A B

C D

Reaction Favorability Scoring

Simple scoring method to suggest predicted reaction feasibility and favorability based on a simplification of Hess’ lawHreaction = (BDEbroken) – (BDEformed)

Estimate change in enthalpy by looking up bond-dissociation energies (BDE)

Apply additional bonuses and penalties for aromaticity and ring strain

Pseudo-Mechanistic Reactions

First step towards more generalized, pseudo-mechanistic reaction modeling is the introduction of “intermediates”

Model breaking a bond in each reactant by separating charge, representative of the bond electrons moving to one atom

Closing the intermediates is then just a matter of matching + and - charges

A B

C D

A+ B-

C- D+

A B

C D

Pseudo-Mechanistic Reactions

Applying general electron-shifting rules on the intermediates before closing them into products provides a lot of power and chemically intuitive results

O- H+O H O

-

H+

O

Azide + Alkyne Example

R1 N N+ N-

R2 C CR3

R1 N+ N N-

R2 C- C+

R3

R1 NN N

C CR2

R3

Diels-Alder Example

C CC C

+

C C

C- CC+ C

+

C- C+

C CC+ C-

+

C- C+

ChemDB Architecture

Client

cdb.ics.uci.edu

chemdb.ics.uci.edu

finger.ics.uci.edu

1. HTTP Reque

st

2. Similarity

Query3.

Similarity Results

4. DB Query

5. DB Result

s

6. HTML

Results

ChemDB Architecture cdb.ics.uci.edu

Linux, 1GB Primary Integration Point Web Server (Apache) Image Server (internal smi2gif.py script) Issue Tracker (Scarab, Tomcat JSP, PostgreSQL

DB) chemdb.ics.uci.edu

MS Windows Server 2003 Database Server (PostgreSQL)

finger.ics.uci.edu Linux, 4GB Similarity Search Server (Internal FINGER module)