Ohio State biophysicist disrupts cellular messages through fragment-based drug design

March 03, 2016

Li employed the AMBER (Assisted Model Building with Energy Refinement) and AutoDock molecular modeling simulation software packages to help define the interactions between those proteins and the strength of their binding at five ???hot spots??? found in each half of the IL-6/IL-6R/GP130 hexamer.

By plugging small molecules, like MDL-A, into any of those hot spots, Li could block the hexamer from forming. So, he examined the binding strength of MDL-A at each of the hexamer hotspots, identifying most promising location, which turned out to be between IL-6 and the first segment, or modular domain (D1), of the GP130.

To design a derivative of MDL-A that would dock with D1 at that specific hot spot, Li used the CombiGlide screening program to search through more than 6,000 drug fragments. So far, he has identified two potential solutions by combining the ???top??? half of the MDL-A molecule with the ???bottom??? half of a benzyl molecule or a pyrazole molecule. These candidates preserve the important binding features of the MDL-A, while yielding molecules with strong molecular bindings that also are easier to synthesize than the original MDL-A.

???While we didn??t promise to have a drug fully developed within the two years of the project, we??re making excellent progress,??? said Li. ???The current research offers us an exciting new therapeutic paradigm: targeting tumor microenvironment and inhibiting tumor stem cell renewal, leading to a really effective way to overcome breast tumor drug resistance, inhibiting tumor metastasis and stopping tumor recurrence.???

While not yet effective enough to be considered a viable drug, laboratory tests on tissue samples have verified the higher potency of the derivatives over the original MDL-A. Team members are preparing for more sophisticated testing in a lengthy and carefully monitored evaluation process.

Li??s project is funded by a grant from the Department of Defense (CDMRP grant number BC095473) and supported by the award of an OSC Discovery Account. The largest funding areas of Congressionally Directed Medical Research Programs (CDMRP) are breast cancer, prostate cancer and ovarian cancer. Another Defense CDMRP grant involving Li supports a concurrent OSU investigation of the similar role that IL-6 plays in causing prostate cancer. Those projects are being conducted in collaboration with Li??s Medicinal Chemistry colleague, Dr. James Fuchs, as well as Drs. Tushar Patel, Greg Lesinski and Don Benson at OSU??s College of Medicine and James Cancer Hospital, and Dr. Jiayuh Lin at Nationwide Children??s Hospital in Columbus.

???In addition to leading the center??s user group this year, the number and depth of Dr. Li??s computational chemistry projects have ranked him one of our most prolific research clients,??? Krishnamurthy noted.

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