Presentation Title

A Novel Technique in Drug Design: Modifying Cdk-2 Inhibitors Through Dynamic Undocking to Treat Deafness

Faculty Mentor

David Hall

Start Date

23-11-2019 10:45 AM

End Date

23-11-2019 11:30 AM

Location

112

Session

poster 4

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

A common side effect of cisplatin (a chemotherapy drug) is acute hearing loss, experienced by 70% of patients. Recent research has indicated that cisplatin distorts the cell cycle and leads to the increased expression of the CDK-2/Cyclin A complex, a protein that kills inner ear cells known as the cochlea. This experiment was aimed at suppressing the CDK-2 complex by computationally enhancing the binding receptivity of certain inhibiting ligands. In order to achieve this, dynamic undocking -- a novel computation technique that analyzed drug binding and conformational changes -- was applied. Traditional docking scores were supplemented in the modification of a wide array of different CDK-2/Cyclin A inhibitors, both directly competing with activation, or allosterically inhibiting the complex. Based on previous literature, it was hypothesized that dynamic undocking would lead to over 15% increases in docking and dynamic undocking scores. To analyze the data, computational modeling tools including but not limited to the Molecular Operating Environment and ChemBioDraw were employed. According to the results, this technique was effective in the modification of all of the ligands, significantly increasing their binding receptivity to CDK-2 and inactivating this protein. This investigation has revealed the possibility of applying dynamic undocking to other flexible ligand-receptor complexes in the future, which can theoretically have the potential to not only treat deafness, but a plethora of other diseases as well.

This document is currently not available here.

Share

COinS
 
Nov 23rd, 10:45 AM Nov 23rd, 11:30 AM

A Novel Technique in Drug Design: Modifying Cdk-2 Inhibitors Through Dynamic Undocking to Treat Deafness

112

A common side effect of cisplatin (a chemotherapy drug) is acute hearing loss, experienced by 70% of patients. Recent research has indicated that cisplatin distorts the cell cycle and leads to the increased expression of the CDK-2/Cyclin A complex, a protein that kills inner ear cells known as the cochlea. This experiment was aimed at suppressing the CDK-2 complex by computationally enhancing the binding receptivity of certain inhibiting ligands. In order to achieve this, dynamic undocking -- a novel computation technique that analyzed drug binding and conformational changes -- was applied. Traditional docking scores were supplemented in the modification of a wide array of different CDK-2/Cyclin A inhibitors, both directly competing with activation, or allosterically inhibiting the complex. Based on previous literature, it was hypothesized that dynamic undocking would lead to over 15% increases in docking and dynamic undocking scores. To analyze the data, computational modeling tools including but not limited to the Molecular Operating Environment and ChemBioDraw were employed. According to the results, this technique was effective in the modification of all of the ligands, significantly increasing their binding receptivity to CDK-2 and inactivating this protein. This investigation has revealed the possibility of applying dynamic undocking to other flexible ligand-receptor complexes in the future, which can theoretically have the potential to not only treat deafness, but a plethora of other diseases as well.