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Virtual Screening P53
Transcript of Virtual Screening P53
Saving time and money The Protein receptor has a pocket, or slot that sits and waits for a properly shaped ligand to slip in. The presence of the Ligand near the receptors binding region causes the receptor to fold around the ligand. Virtual screening and docking holds the Receptor rigid and moves the ligand This is the Lock and Key Paradigm But recent studies have been successful in using VS on dynamic receptors See the development of Raltegravir. A HIV Integrase Inhibitor. The docking took place against snapshots from a Molecular dynamics simulation. Some proteins have rigid structure. Some proteins are molten globules Some proteins are intrinsically disordered Docking on snapshots of dynamic receptors may work because the timescale of ligand docking is faster than the timescale of protein folding. Can this work on Intrinsically Disordered Proteins? Rigid Disordered Intrinsically Disordered Proteins (IDPs) IDPs act as "Hubs" interacting with many different proteins. Common in signal transduction (70% of proteins involved in signaling) about 80% of all proteins associated with cancer Ability to screen against IDPs could yield many important drug targets. P53 So called "guardian of the genome" detects DNA damage and triggers cell death (apoptosis) TransActivation Domain (TAD) is Intrinsically disordered inhibition of P53 is implicated in Cancer two seperate known binding regions:
MDM2 (between Q16-L26)
RPA70 (between A39-G59) An antogonist binding to either location should inhibit a cancer cells ability to prevent apoptosis Ligand models were obtained from the NCBI diversity set
over 1800 small molecules representitive of many classes of compounds These are screened against the 8 most common structures of P53 in both regions using Autodock Vina And the results are: MDM2 region with about 8.7 kcal/mol RPA70 region with about 9.2 kcal/mol Next step:
Gather more data
send off to Test in vitro if we can find weak binding lead for each region, we can link them together for increased affinity. Thank you to:
Dr. Marty Ytreburg (Lead Investigator)
Dr. Gary Daughdril (For the idea)
Dr. Stepan Kashtanov (For high weight P53 structures)
Dr. Konrad Shyu (For Autodock suggestions)