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SePreSA™— a Server for the Prediction of Population Susceptible to Serious Adverse Drug Reaction

User's Manual

What does SePreSA™ provide for you?

Our server successfully predicted the susceptibility population of oseltamivir (Tamiflu®) induced neuropsychiatric disorders.

Oseltamivir, an anti-flu drug, whose active form binds to the active site of human cytosolic sialidase. A rare polymorphism near the binding pocket may enhance this unexpected binding and might increase susceptibility to oseltamivir-induced neuropsychiatric disorders.[1]

Now we upload the active form of oseltamivir to show how to use our server.

The flow diagram of using our server

1. Login

For registered user, you can sign in with your username and password.

We use a system of user management in order to give every user a separate space to handle their uploaded drugs. Guests can register freely and easily by clicking on the "Register" button.

2. Upload a drug molecule

After logging in, you will see a page which allows you to upload a drug molecular.

Click on the "Browse" button to upload a drug file. In this example, we choose oseltamivir carboxylate, an active form of the Tamiflu®. The drug should not be planar for it won't raise reasonable assessment of the interaction strength of this drug-protein interaction. The file should be in mol2 format with extension name of mol2/ml2 and make sure hydrogens and electricities are added (How to generate a mol2 file?). In order to protect the accessibility of other users, your uploaded file should not exceed the limitation of 18 kb. You can download our sample file naphthylamine.mol2 and upload it for a quick test.

3. Wait for the interactome of your drug molecule to be constructed (3-5 hours)

When your drug molecule file is uploaded correctly, our program starts to put your molecule in a queue automatically. You can click on the "Refresh" link to see the progress. If you upload our example file, it takes only several minutes to complete, however, for oseltamivir carboxylate it will take much longer.

4. Check which ADR targets tend to interact with your molecule

After clicking on the "Detail" button, you will first see detailed information of this drug. The "N/A" symbol in some fields does not hamper the result.

You will not see the "Interactome of your molecule toward the ADR targets" unless the progress rate reaches 100%.

The Docking Score fields represent the interaction strength of the molecule to the protein. The scores were converted into Z-score and Z'-score. The drug molecule tends to interact with the protein if Z'-score is less than -0.5 and the Z-score is less than -1.2. Z'-scores less or greater than -0.5 are presented in purple/black font, whereas Z-scores less or greater than -1.2 are presented in red/blue font.

According to our algorithm, please note if the distinct number of your uploaded ligands is less than 2, the Z'-score will not be calculated (displaying "N/A") and when you click on a reaction page, it might report an error. So please upload two or more distinct ligands to make sure the Z'-scores can be correctly calculated.

5. Check which AA residuals interact with your molecule

Click on the "Result" button to visualize the binding pattern.

In the left table, you will see residues within 6.4Å of the drug molecule, which were also colored in the right Applet. Clicking on the residue in left table allows you to view residues within 6.4Å of the very residue you have clicked.

You can choose "label on/off" to show/hide the labels of AA residues according to the left table.

If there are any SNPs within 6.4Å of binding pocket, their detailed information will be shown in the bottom table.

6. Check the polymorphism information of these AA residuals among different population

Click on the "SHOW REPORT" button to show populations with putative diversity in binding strength of this drug-SADR target interaction.

In this report, you will see three levels of warnings.

Level I warning displays polymorphisms known to change protein function.
Level II warnings is presented if the function of the polymorphisms within 6.4Å of the drug molecule are unidentified.
Level III warnings lists polymorphism information other than information listed in Level I/II warnings.

7. Log out

If you want to logout or switch to another account, you can click "Log out" in the left navigation menu, or close your browser, the session will automatically end.

References:

1 Li, C.Y. et al. A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir. Cell Res 17, 357-62 (2007).