Drug Designing: Open Access
Open Access

Novel ribonucleotide reductase inhibitor development: A story from virtual screening to inhibition mechanism

International Conference and Exhibition on Computer Aided Drug Design & QSAR

October 29-31, 2012 DoubleTree by Hilton Chicago-North Shore, USA

Leila Su

Posters: Drug Design

Abstract :

As a key enzyme in DNA synthesis, RNR is involved in tumor growth, metastasis, and drug resistance effect. Effective and clinically useful RNR inhibitors have yet to be developed as the current RNR inhibitors have shortcomings of short half-life, drug resistance, and iron chelation. We have developed a class of effective RNR inhibitors using structure-based and mechanism- based approaches. A novel ligand binding pocket on the RNR small subunit was proposed by computer modeling and verified by site-directed mutagenesis and NMR techniques. A hit compound was identified against the pocket by virtual screening an NCI diverse small molecule database representing of the NCI library of 250,253 compounds. Following several rounds of lead optimization, the novel RNR inhibitor COH29 with sub-micromolar range inhibition was designed and developed. COH29 was a potent inhibitor of both recombinant and cellular human RNR enzymes, which overcame resistance to HU and Gem in resistant cell lines, and effectively inhibited proliferation of most cell lines in the NCI 60 human cancer panel, most notably ovarian cancer and leukemia. Normal fibroblasts were far less sensitive to the cytotoxic effects of COH29 compared to the RNR inhibitors currently in clinical use. In murine tumor xenograft models COH29 treatment significantly reduced tumor growth compared to vehicle. Site-directed mutagenesis, NMR, and surface plasmon resonance biosensor studies confirmed COH29 bound at the proposed ligand binding pocket and may block assembly of the RRM1-RRM2 quaternary structure. Our study suggested COH29 represents a promising new class of RR inhibitors and was granted a US Patent.

Biography :

Leila Su has completed her Ph.D in Biochemistry in 1995 from Florida State University and postdoctoral studies from University of Chicago in 1997. She is assistant research professor in City of Hope national cancer center. She has published more than 11 peer-reviews papers with 6 listed as the first or co-first authors and has two patents granted by US patent office.