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Receptor-Ligand Interactions

Terminology#

  • receptor: ์ƒ๋ฌผํ•™์  ์‹œ์Šคํ…œ์— ํ†ตํ•ฉ๋  ์ˆ˜ ์žˆ๋Š” ์‹ ํ˜ธ๋ฅผ ์ˆ˜์‹ ํ•˜๊ณ  ๋ณ€ํ™˜ํ•˜๋Š” protein์œผ๋กœ ๊ตฌ์„ฑ๋œ ๋ฌผ์งˆ
  • ligand: ์ƒ๋ฌผํ•™์  ๋ชฉ์ ์„ ์ˆ˜ํ–‰ํ•˜๊ธฐ ์œ„ํ•ด ํŠน์ • molecule๊ณผ complex๋ฅผ ํ˜•์„ฑํ•˜๋Š” ๋ฌผ์งˆ

Interactions#

ligand๋Š” ์ผ๋ฐ˜์ ์œผ๋กœ target protein์˜ ํŠน์ • site์— ๊ฒฐํ•ฉํ•˜๋ฉฐ ๊ฒฐํ•ฉ์€ ionic bonds, hydrogen bonds ๋ฐ Van der Waals forces์™€ ๊ฐ™์€ non-covalent binding์— ์˜ํ•ด ์œ ์ง€๋˜๋ฉฐ, solvent effects์— ์˜ํ–ฅ์„ ๋ฐ›์Šต๋‹ˆ๋‹ค. ๊ฒฐํ•ฉ์€ ์ผ๋ฐ˜์ ์œผ๋กœ target protein์˜ conformational isomerism(conformation)์˜ ๋ณ€ํ™”๋ฅผ ์ดˆ๋ž˜ํ•ฉ๋‹ˆ๋‹ค. protein์˜ conformation์€ ํ•ด๋‹น protein์˜ function์„ ์˜๋ฏธํ•  ์ˆ˜ ์žˆ์œผ๋ฏ€๋กœ ๋”ฐ๋ผ์„œ conformation์˜ ๋ณ€ํ™”๋Š” function์˜ ๋ณ€ํ™”๋ฅผ ์˜๋ฏธํ•  ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค. ๊ด€๋ จ๋œ ion channel๋˜๋Š” enzyme ๋“ฑ์˜ ๋ณ€๊ฒฝ๋œ ํ–‰๋™์„ ์ดˆ๋ž˜ํ•˜๋Š” ๊ฒฝ์šฐ ์ƒ๋ฆฌํ•™์ ์œผ๋กœ ์ค‘์š”ํ•ฉ๋‹ˆ๋‹ค.


์ด๋Ÿฌํ•œ ์ƒํ˜ธ์ž‘์šฉ์„ ์ด์šฉํ•˜์—ฌ, target receptor์˜ ์—ญํ• ์„ ์ €ํ•ดํ•˜๊ฑฐ๋‚˜ ์ด‰์ง„์‹œํ‚ค๋Š” ligand๋ฅผ ์ฐพ์•„ ์›ํ•˜๋Š” ์ƒ๋ฆฌ ๋ฐ˜์‘์„ ์ด๋Œ์–ด๋‚ด๋Š” ์•ฝ์„ ๋งŒ๋“ค ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค. ์•ฝํšจ๋Š” binding affinity์™€ ligand efficacy ๋“ฑ ๋ชจ๋‘์˜ ๋ณต์žกํ•œ ์ƒํ˜ธ์ž‘์šฉ์˜ ๊ฒฐ๊ณผ์ด๋ฏ€๋กœ, ์•ฝํšจ๊ฐ€ ์žˆ๋Š” ๋ฌผ์งˆ์„ ํ•œ ๋ฒˆ์— ์ฐพ๊ธฐ ์–ด๋ ต์Šต๋‹ˆ๋‹ค.

Docking#

DTI(Drug-target interaction)

MMGBSA(Molecular Mechanics Generalized Born Surface Area) binding affinity(kcal/mol ๋‹จ์œ„)๋ฅผ ์ถ”์ •ํ•  ๋•Œ ์‚ฌ์šฉ๋˜๋Š” ๊ณ„์‚ฐ ๋ฐฉ๋ฒ•

MMPBSA(Molecular Mechanics Poisson-Boltzmann Surface Area) binding free energy๋ฅผ ์ถ”์ •ํ•  ๋•Œ ์‚ฌ์šฉ๋˜๋Š” ๊ณ„์‚ฐ ๋ฐฉ๋ฒ•

PLIP(Protein-Ligand Interaction Profiler)

privileged scaffold๋Š” ์•Œ๋ ค์ง„ ์•ฝ๋ฌผ์ด๋‚˜ ์ƒ๋ฌผํ•™์  ํ™œ์„ฑ ํ™”ํ•ฉ๋ฌผ์˜ ํŠน์ • ๋ฐฐ์—ด ์‚ฌ์ด์—์„œ ํ†ต๊ณ„์ ์œผ๋กœ ๋ฐ˜๋ณต๋˜๋Š” ๋ถ„์ž ๊ตฌ์กฐ ๋˜๋Š” ํ™”ํ•™์  moiety์ธ๋ฐ, ์ด๋Ÿฌํ•œ ์š”์†Œ๋Š” ์ƒˆ๋กœ์šด ํ™œ์„ฑ ์ƒ๋ฌผํ•™์  ํ™”ํ•ฉ๋ฌผ ๋˜๋Š” ํ™”ํ•ฉ๋ฌผ ๋ผ์ด๋ธŒ๋Ÿฌ๋ฆฌ๋ฅผ ์„ค๊ณ„ํ•˜๊ธฐ ์œ„ํ•œ ๊ธฐ์ดˆ๋กœ ์‚ฌ์šฉํ•  ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค.

Reference#

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