Investigating the Structure of Potential New Drug to Treat Sickle Cell Anemia through Inhibition of the Polymerization of Hemoglobin S​

Sickle cell anemia is a hematologic disorder impacting over 15 million people worldwide. It is caused by a single point mutation in the gene hemoglobin-Betha, where a glu group is replaced by val (GAG --- GTG) in the seventh codon (glu7val) of chromosome 1. In this study, we are comparing the anti-sickling properties of drugs in varied conditions in order to create a drug that is effective in an O2-independent manner and with a 1:1 stoichiometry for lower dosage purposes. We used Pymol and Jmol to compare the structures of the aldehydes GBT-440 and VZHE-039, which interact on the same binding site to treat sickle cell disease. GBT-440’s bulkiness allows it to have a 1:1 stoichiometry, while VZHE-039’s solubility is due to its interaction with the hemoglobin’s alpha cleft, allowing it to be O2-independent. We identified the pyridine and pyrazole structure from GBT-440 and the methyl hydroxy moite from VZHE-039 as key structures, and created a hypothetical new drug, a hybrid of VZHE-039 and GBT-440. The pose predicted would allow the drug to interact with the sickled hemoglobin in a 1 to 1 ratio and in an O2-independent manner.https://nsuworks.nova.edu/protein_modeling_reports/1002/thumbnail.jp

Creating a Learning Model Where Students Practice the Scientific Process Through Protein Modeling

Based on the CREST (Connecting Researchers, Educators, and STudents) model undergraduate students at Nova Southeastern University (NSU) cooperated in teams through a specially designed Honors Seminar Course titled, “Introduction to Protein Modeling”. This Course-based Undergraduate Research Experience (CURE) brought together groups of undergraduate students early in their studies to have authentic research and presentation experiences. This course was open to all students in NSU’s Farquhar Honors College regardless of their major, academic level or previous college level experience with science or protein modeling. Out of 15 registered students, seven of them were first semester freshmen, one was a sophomore, three were juniors, and four were seniors. Most of the students were Biology or Behavioral Neuroscience Majors. However, there was one of each of the following four majors: Dance, Exercise and Sport Science, Marine Biology, and Pre-Nursing. The students were divided into five groups of three, each consisting of a mix of freshmen and upper-level students. Here we present the design and results of a course that provided students with early access to a course-based research experience using various protein bioinformatics tools (Jmol, Pymol, Autodoc Vina, and the Protein Data Bank). Students were shown previously completed projects as part of the CREST Program available on the Program’s website: https://cbm.msoe.edu/crest/new9_2021.php. To support CURE sustainability, we used an interdisciplinary team-teaching approach, with distributed leadership and the support of the University’s Honors College in the development of this course. Students worked collaboratively during class meetings to identify a protein molecular story that they wanted to research and describe using molecular modeling tools, including the development of a 3-D model. At the midterm, the student groups shared their progress and received feedback from the faculty and their peers. Students continued to revise their modeling projects and received additional feedback one month later. At the end of the semester each team presented their final projects with components that included a protein model description sheet, poster, and oral presentations. Student projects included molecular stories related to MMP 12, cystic fibrosis transmembrane regulator, marine bacterial laminarinase, sickle cell anemia, and iron acquisition in E. coli related to TonB/TonBox binding. Through interacting with the primary literature, course materials, and using protein modeling tools, students gained an introduction to the scientific process and applied it to better understand molecular mechanisms. During this process, students also learned to explain these processes to themselves and others through constructing presentations and model descriptions. Student learning gains were documented by using the RISC (Research on the Integrated Science Curriculum) Survey