Optimization of a Complement Component 5 Inhibitor with Hydrophobic Cluster Modification

Ella AlanFollow

School Name

South Carolina Governor's School for Science and Mathematics

Grade Level

12th Grade

Presentation Topic

Biochemistry

Presentation Type

Mentored

Abstract

The complement system is an important part of the immune system that functions to induce a series of inflammatory reactions to enhance the abilities of antibodies. The protein complement component 5 (C5) is a validated drug target within the complement pathway. The effects of dysregulation of the complement pathway contributes to the clinical symptoms of many conditions, including myasthenia gravis and endometriosis, and C5 inhibitors have proved effective in treating these effects. Currently, many inhibitors are large molecules intravenously administered; small molecule inhibitors are currently being developed. M. Zhang et. al. discovered that 1-phenyl-3-(1-phenylethyl) urea derivatives act as small molecule inhibitors of the complement system; this structure was further modified by K. Jendza et. al. Jendza et. al was also able to suggest the molecular mechanisms by which the compound inhibited C5. The molecule’s lipophilic side chain rests within a hydrophobic pocket within C5; the researchers concluded that there exists a need for the lipophilic side chain to properly fill this space. The goal of this research was to extend this side chain and thus optimize how it fits within the hydrophobic pocket of C5. Three main modifications were made: extension of the terminal carbons with methyl groups, the use of fatty acid mimicking structures, and the addition of ringed structures. The computational software AutoDock VINA was used to compare binding affinities between different iterations of the drug; it was found that the addition of ringed extensions gave the best binding affinities.

Location

HSS 202

Start Date

4-2-2022 11:30 AM

Presentation Format

Oral Only

Group Project

No

COinS
 
Apr 2nd, 11:30 AM

Optimization of a Complement Component 5 Inhibitor with Hydrophobic Cluster Modification

HSS 202

The complement system is an important part of the immune system that functions to induce a series of inflammatory reactions to enhance the abilities of antibodies. The protein complement component 5 (C5) is a validated drug target within the complement pathway. The effects of dysregulation of the complement pathway contributes to the clinical symptoms of many conditions, including myasthenia gravis and endometriosis, and C5 inhibitors have proved effective in treating these effects. Currently, many inhibitors are large molecules intravenously administered; small molecule inhibitors are currently being developed. M. Zhang et. al. discovered that 1-phenyl-3-(1-phenylethyl) urea derivatives act as small molecule inhibitors of the complement system; this structure was further modified by K. Jendza et. al. Jendza et. al was also able to suggest the molecular mechanisms by which the compound inhibited C5. The molecule’s lipophilic side chain rests within a hydrophobic pocket within C5; the researchers concluded that there exists a need for the lipophilic side chain to properly fill this space. The goal of this research was to extend this side chain and thus optimize how it fits within the hydrophobic pocket of C5. Three main modifications were made: extension of the terminal carbons with methyl groups, the use of fatty acid mimicking structures, and the addition of ringed structures. The computational software AutoDock VINA was used to compare binding affinities between different iterations of the drug; it was found that the addition of ringed extensions gave the best binding affinities.