title: Unlocking the binding and reaction mechanism of hydroxyurea substrates as biological nitric oxide donors.
abstract: Hydroxyurea is the only FDA approved treatment of sickle cell disease. It is believed that the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood; however, the exact details of this are still unclear. In the current work, we investigate the atomic level details of this process using a combination of flexible-ligand/flexible-receptor virtual screening coupled with energetic analysis that decomposes interaction energies. Utilizing these methods, we were able to elucidate the previously unknown substrate binding modes of a series of hydroxyurea analogs to hemoglobin and the concomitant structural changes of the enzyme. We identify a backbone carbonyl that forms a hydrogen bond with bound substrates. Our results are consistent with kinetic and electron paramagnetic resonance (EPR) measurements of hydroxyurea-hemoglobin reactions, and a full mechanism is proposed that offers new insights into possibly improving substrate binding and/or reactivity.
authors.affiliation: Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery, and Delivery, University of South Floridar, Tampa, Florida 33620, USA.
authors.forename: Sai Lakshmana
authors.initials: SL
authors.lastname: Vankayala
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Hargis
authors.forename: H Lee
authors.initials: HL
authors.lastname: Woodcock
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D006454:Hemoglobins; D008024:Ligands; D020030:Nitric Oxide Donors; D006918:Hydroxyurea