Drug Discovery
Advisor(s)
Dr. John Thurmond, Illinois Mathematics and Science Academy
Location
Room B116
Start Date
26-4-2019 10:45 AM
End Date
26-4-2019 11:00 AM
Abstract
Anastrozole is a commercial drug used to treat breast cancer in postmenopausal females. It targets the protein Cytochrome P450 19A1 which cleaves androgen to produce estrogen which can cause breast cancer. The focus of our project was to alter the chemical structure of the drug and improve its properties to inhibit the protein Cytochrome P450 19A1 from producing estrogen more effectively. We began by studying how the drug binds to protein Cytochrome P450 19A1 and prevents it from functioning. A molecular representation of this bindage was not online, so we studied to protein ligand properties of Cytochrome P450 19A1 and drew it ourselves using the computer programs ACD ChemSketch and Molinspiration. We compared this structure to that of the drug Androstenedione with the same target protein as it had a molecular representation of its binding on the PDB website. Using SeeSAR, we used Androstenedione’s PDB and substituted it with the Anastrozole molecule so that we had a 3D model of Anastrozole molecule binded to the common target protein, Cytochrome P450 19A1. We then altered the molecule of Anastrozole by altering the structure in various different ways. As of right now, the most effective alteration is one that has nitrogen atoms exchanged for phosphorus atoms in the molecule to improve the binding affinity to Cytochrome P450 19A1. Specifically, we exchanged nitrogen atoms to phosphorus atoms to get our binding affinity boundary to 0.04 nM to 3.78 nM from the original 4488.02 nM to 445911.64 nM. After concentrating on the estimated affinity, we directed our focus towards torsion quality, intermolecular clash, and intramolecular clash. By significantly improving the molecule’s binding affinity to Cytochrome P450 19A1, we have altered the Anastrozole drug to improve its effects on patients.
Drug Discovery
Room B116
Anastrozole is a commercial drug used to treat breast cancer in postmenopausal females. It targets the protein Cytochrome P450 19A1 which cleaves androgen to produce estrogen which can cause breast cancer. The focus of our project was to alter the chemical structure of the drug and improve its properties to inhibit the protein Cytochrome P450 19A1 from producing estrogen more effectively. We began by studying how the drug binds to protein Cytochrome P450 19A1 and prevents it from functioning. A molecular representation of this bindage was not online, so we studied to protein ligand properties of Cytochrome P450 19A1 and drew it ourselves using the computer programs ACD ChemSketch and Molinspiration. We compared this structure to that of the drug Androstenedione with the same target protein as it had a molecular representation of its binding on the PDB website. Using SeeSAR, we used Androstenedione’s PDB and substituted it with the Anastrozole molecule so that we had a 3D model of Anastrozole molecule binded to the common target protein, Cytochrome P450 19A1. We then altered the molecule of Anastrozole by altering the structure in various different ways. As of right now, the most effective alteration is one that has nitrogen atoms exchanged for phosphorus atoms in the molecule to improve the binding affinity to Cytochrome P450 19A1. Specifically, we exchanged nitrogen atoms to phosphorus atoms to get our binding affinity boundary to 0.04 nM to 3.78 nM from the original 4488.02 nM to 445911.64 nM. After concentrating on the estimated affinity, we directed our focus towards torsion quality, intermolecular clash, and intramolecular clash. By significantly improving the molecule’s binding affinity to Cytochrome P450 19A1, we have altered the Anastrozole drug to improve its effects on patients.