2017 Stetten Lecture--Computing Cures: Discovery Through the Lens of a Computational Microscope

Masur Auditorium Clinical Center (Building 10)
National Institutes of Health
Bethesda, Maryland

Start Date: 10/25/2017 3:00 PM

End Date: 10/25/2017 4:00 PM

Rommie Amaro

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Speaker: Rommie E. Amaro, Ph.D.
Professor and Shuler Scholar
Department of Chemistry and Biochemistry
University of California, San Diego
Director, National Biomedical Computation Resource

Rommie Amaro applies her deep understanding of chemistry and engineering to computationally model how proteins change shape and interact. Her goal is to develop new computer simulation techniques to aid the discovery of small molecules that impact protein function—and can treat diseases such as cancer.

Amaro and her colleagues are currently focused on p53, a key molecule in preventing tumors. In its active form, four molecules of p53 link together to form a tetramer. Normally, p53 detects damaged DNA and the tetramer clamps onto specific genes to shut down cell division. This action prevents the defective DNA—which can cause cancer—from being passed to a new generation of cells.

2017 Stetten Lecture posterIn contrast, mutant versions of p53 allow cells to grow out of control, increasing the risk of cancer. Nearly half of human tumors contain mutant p53. Because of this, p53 is a popular target for potential anti-cancer drugs.

Using structural data, Amaro and her team simulated the movements of p53. This work revealed a binding pocket in the protein’s core that only opens at certain times. Finding this pocket helped to explain how a potential new drug, now in clinical trials, produces its anti-cancer effect.

Amaro and her colleagues are now developing dozens of small molecules that can bind in the pocket and reactivate p53. Their work formed the basis for a biotech startup, Actavalon, Inc., that Amaro cofounded to translate the research into a new anti-cancer drug.

Amaro’s team is beginning to model the movements of ever larger and more flexible structures. Recently, her group simulated how p53 behaves as a tetramer bound to different sequences of DNA. This work showed how p53 can change its “grip” depending on the DNA sequence. It also revealed the roles of all portions of the p53 molecule, adding to the understanding of this molecule and opening new avenues for drug discovery.

Amaro received her B.S. in chemical engineering in 1999 and her Ph.D. in chemistry in 2005, both from the University of Illinois, Urbana-Champaign. She was an NIH postdoctoral fellow under J. Andrew McCammon at University of California, San Diego (UCSD). In 2016, she was named the American Chemical Society Kavli Emerging Leader in Chemistry and also received the Corwin Hansch Award, which is given annually to a scientist under the age of 40 who contributes significantly to the field of computer-aided drug design. Amaro also received a 2010 Presidential Early Career Award for Scientists and Engineers and a 2010 NIH Director's New Innovator Award.

Amaro leads two NIGMS-supported resources at UCSD. She directs the National Biomedical Computation Resource​​ and co-directs the Drug Design Data Resource. She also serves on various advisory boards, including the NIH Common Fund program, Illuminating the Druggable Genome; the NIGMS-supported HIV Interaction in Viral Evolution Center​; and the NIGMS-supported National Resource for Automated Molecular Microscopy.

NIGMS has supported Amaro’s work since 2006 under P41GM103426, U01GM111528, R25GM114821, and F32GM077729.