In Silico Design of Selective Estrogen Receptor Modulators

from Triazoles and Imines

Joey SalisburyDr. John C. Williams

Small Molecules/Large Molecules SeminarSummer 2008

How to Design DrugsUsing a PlayStation 3

Estrogen Receptor αregulates gene expression depending on cell type

4-hydroxytamoxifen(a selective estrogen receptor modulator)

Estradiol (natural estrogen receptor ligand)

Estradiol

Why look for selective estrogen receptor modulators (SERMs)?

• Some are good:-- Postmenopausal osteoporosis responds favorably to SERMs.-- All SERMs decrease breast cancer risk, and tamoxifen is mainly used for its ability to inhibit growth in estrogen receptor-positive breast cancer.-- Cholesterol and triglycerides levels respond favorably.

• Some are bad: -- Deep venous thrombosis - the risk may be elevated in at least some SERMs.-- Hot flashes are increased by all SERMs.-- Tamoxifen may increase endometrial carcinoma risk

• The more SERMs we know, the better we can understand their action and develop more positive ones.

The Beginning of Future SERMs?

Estradiol

SMILES (Simplified Molecular Input Line Entry Specification)

c4ccc(c2nnn(c1ccccc1)c2c3ccccc3)cc4

Combinatorial Chemistry

Consider taking 21 different functional groups and placing them in every possible combination at R1, R2, and R3.

Creating this library of chemicals, we see there are:

213 = 9,261 combinations

Combinatorial Chemistry

Not impressed? Ok, well take those compounds and add a second functional group somewhere on the first one.

With 21 possible functional groups, that means

(213)2 = 85,766,121 combinations

ADME/Tox Filter• Eliminate compounds in our library which have poor ADME/Tox qualities• Lipinski’s rule of 5• Not more than 5 hydrogen bond donors• Not more than 10 hydrogen bond acceptors• A molecular weight under 500 g/mol• A partition coefficient log P less than 5

• Done online, this step is fast• 10,000 compounds take <1 min• 10-90% of compounds eliminated

Going 3D• Before we do our next step, we must convert our file containing SMILES formula into 3D structures• To do this, you can download for free online the program MarvinBeans from ChemAxon

Docking with eHiTS(Electronic High-throughput Screening)

EstradiolEstrogen Receptor α

Arylphosphonium saltscomplexed with AChE

What about PlayStation 3?• All of this could be done on a PS3 (you just have to install Linux onto it)• SimBioSys, the company that makes eHiTS, has made a special version of eHiTS which takes advantage of the PlayStation 3’s Cell Broadband Engine processor.• Can run 30x faster than on a traditional processor! • What would take us a month could be done in a day!

Conclusions• Large numbers of small molecules can be generated and stored on a computer in SMILES format and then converted to 3D structures with free online applications.• X-ray structures of large molecules can be found on the Protein Data Bank.• We can attempt to predict the interaction between small molecules and a protein using docking programs such as eHiTS in order to design new drugs.

THE ENDTHANK YOU