Exercise 1: Database searching

The purpose of this exercise is to familiarize you with database searching for information relevant to drug development. You will work with 3 molecules. 1. Sildenafil
2. CC(=O)N1CCN(CC1)C2=CC=C(C=C2)OCC3COC(O3) (CN4C=CN=C4)C5=C(C=C(C=C5)Cl)Cl

3.

(Molecule 2 is given by its SMILES and molecule 3 by its 2D structure.) Go to PubChem http://pubchem.ncbi.nlm.nih.gov/ and gather the information requested below: 1) For molecule 1, write the name under Compound. For molecules 2 and 3, go to Chemical structure search Identity-Similarity, where you insert the SMILES and draw the structure, respectively. Write down the name and draw the 2D structure of each molecule (select the first one in the list, if you have several molecules under the same name or structure). 2) Click on the name or the structure. You are now directed to the Compound Summary. What is the Pharmacological Action of each compound? Based on the Properties computed from Structure in the Compound Summary, and on the Lipinksis Rule of 5, evaluate if the compounds are druglike or non-druglike. 3) Click on BioActivity Analysis BioActivity-this compound (Icon with two rings on the top right) How many bioassays has each molecule been tested on? On how many is each molecule active? 4) Go to Structure-Activity and click on Add Similar Compounds.

 How many similar compounds did you find? What is the Tanimoto coefficient of the cluster? Which compound is the most similar to your query molecule? Which is the common substructure of the cluster? Choose a pair from the compound cluster, for which, structural similarity translates to activity similarity. 5) Click on a one BioAssay that your query molecule is active on. How many other compounds have been tested and found active on the same?

Exercise 2: Focused library design

The purpose of this exercise is to show you how you can create a focused library of compounds around the structure of an interesting query. Go to the ZINC database http://zinc.docking.org/ and perform the following steps: 1) Click on Search and Browse 2) Paste the SMILES of the one of the three compounds from the previous exercise. 3) Click on 70% Tanimoto similarity and Run the Query 4) Repeat the search with the following restrictions: a. Compounds with Drug like properties b. Compounds that can be delivered immediately How many compounds do you find in each search? 5) Download the SDFiles and keep them in your folder for later use.