Date of Completion

2023

Document Type

Thesis

Degree Name

Bachelor of Science in Biochemistry

Keywords

CD4 T-cell receptor, Sec61 channel, translocation, cyclotriazadisulfonamide

Abstract

The CD4 T-cell receptor is vital in the infection of the human immunodeficiency virus (HIV) in CD4+ cells. Cyclotriazadisulfonamide (CADA) are macrocyclic compounds that were found to exhibit a unique mechanism in preventing HIV infection, which is through expression inhibition of the CD4 T-cell receptor. One of the proposed mechanisms of CADA’s CD4 receptor inhibition is by blocking the gates of the Sec61 channel, preventing its translocation. However, CADA has poor solubility and bioavailability. Hence, the study aimed to design CADA analogs that would exhibit good binding to the Sec61 channel, have good bioavailability, and low toxicity. CADA analogs were designed using SeeSAR, while Avogadro and Meeko were utilized for the 3D configuration and placing of pseudoatoms, respectively. AutoDock Vina version 1.2.4 was used to determine the binding energies of these analogs following the docking protocol for macrocycles. Among the 113 analogs designed, 93 were found to theoretically display better binding to the Sec61 channel than CADA. The enzyme-ligand interactions were analyzed to explain the forces contributing to the displayed binding energies. The top 3 binding analogs are WM038, WM039, and WM041, with

binding energies of -12.73 kcal/mol, -12.21 kcal/mol, and -11.98 kcal/mol, respectively. Moreover, among these 113 analogs, 33 were considered bioavailable. Toxicity prediction using online prediction tools yielded analogs JGL023, JGL024, and JGL032, and JGL047 as the study’s proposed drug candidates. The results of this study serve as a new perspective towards developing drugs that inhibit HIV entry, specifically the pharmacologic potential of CADA.

First Advisor

Margel C. Bonifacio

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