Abstract:
Reactive oxygen species (ROS) are by-products of cellular aerobic metabolism, which play a crucial role in the development of multiple diseases such as cancer. ROS are generated by various enzymes, including respiratory complexes such as respiratory complex III (a.k.a. bc1 complex). The current study spanned multiple disciplines, where we first studied the electron transfer (ET) reactions at the atomistic level between the different redox pairs in the bc1 complex. We discovered that a key phenylalanine residue (Phe90) controls the ET rate between heme bL and heme bH. Additionally, we discovered an allosteric binding site (NQ-site) that is in close proximity to the Phe90 residue space. Hence, we proposed a novel anticancer mechanism by binding ET-modulating agents at the newly discovered NQ-site in the bc1 complex, thereby controlling the conformation of the Phe90 and the cellular total ROS levels. Our proposed mechanism would lead to a reduction in ET rate between heme bL and heme bH, ultimately increasing the cellular ROS levels, triggering apoptosis in the cancer cells. To explore our proposed mechanism, we performed extensive virtual screening of 1,489,806 ligands of the ZINC database against Qo, Qi, and NQ sites of the bc1 complex and obtained 272 patented ligands that bind preferentially at the NQ-binding site compared to Qo and Qi sites. Biochemical assays for the top hit ligands for their ROS-regulatory and cytotoxic activities against breast cancer MCF7 and MDA-MB-231 cells led to the discovery of potential ROS up-regulator compounds that show promising cytotoxic activities. Furthermore, we found that the lead hit ROS up-regulator shows a selective cytotoxic activity against MCF7 and MDA-MB-231 compared to the healthy mammary epithelial MCF10a cells.
Biography:
Dr. Muhammad Hagras received his bachelor's degree from Ain Sham University - Pharmacy College in Egypt. Then, Dr. Hagras received his master's degree in the pharmaceutical and chemical sciences program at the University of the Pacific in Stockton, California. Afterward, Dr. Hagras received his doctoral degree in the biophysics department at the University of California, Davis, where he worked under supervision of Dr. Alexei Stuchebrukhov on simulating electron transfer reactions in multiple respiratory complex proteins. Dr. Hagras had his first postdoctoral position at NYU Shanghai, where he worked on the excited states dynamics under the supervision of Dr. William Glover. Then, Muhammad joined MIT for a second postdoctoral position, where he collaborated with the Merck pharmaceutical company under the supervision of Dr. Bernhardt Trout, studying the transition states of the oxidation reactions of the different cysteines in the human papillomavirus with the various reactive oxygen species. Dr. Hagras accepted an assistant professor position at the University of Health Sciences and Pharmacy in St. Louis in 2021, where his research interests span many fields, from computational studies to developing novel anticancer drugs.
Seminar Series by the NYU-ECNU Center for Computational Chemistry at NYU Shanghai
This event is open to the NYU Shanghai, NYU, ECNU community and the computational chemistry community.