Kev Ntsuam Xyuas Virtual thiab Cov Hluav Taws Xob Hluav Taws Xob Simululation ntawm cov cholesterol Ester Hloov cov protein los ntawm ntuj tsim khoom inibitors ⅱ

 

2 cov txiaj ntsig

2.1 Kev tshawb nrhiav cov qauv protein

Tam sim no, muaj 3 Crystal qauv ntawm cetp protein hauv pdb database (2obd, 4f2a). Cov qauv siv lead ua qauv siv nyob rau hauv txoj kev kawm no muaj kev daws teeb meem siab tshaj plaws thiab ua ke nrog cov haujlwm uas muaj peev xwm mus txog ib qib Nanomolar, thiab kev daws teeb meem ntawm 2.59. Txoj haujlwm uas cov protein thiab cov me me molecule inibitor khi yog kuj tsuas yog khi hnab ris ntawm cov protein. Cov npoo ntawm hnab tshos yog qhia hauv daim duab 1a. Nws tuaj yeem pom tau tias muaj ib lub hnab hydrophobic loj loj hauv cov me me molecule khi txoj haujlwm. Yog li ntawd, rau cov hnab tshos loj no,
Tus qauv-raws cov tshuaj ntsuam virtual tau ua. Lub cim ntawm docking daim phiaj daim phiaj yog nyob ntawm lub hnab tshos thaj chaw uas cov me molecule inhibentor nyob. Qhov chaw ntawm Docking Daim phiaj taw tes yog teeb tsa crystallization lasigand lub thawv sab nraud tau teeb tsa rau 10 Å3, raws li qhia hauv daim duab 1B.

 

Cistanche zoo suplplements

 

 

2.2 kev tshuaj ntsuam virtual raws li docking

Raws li cov hnab ris saum toj no, ntau cov puag ncig ntawm kev tshuaj ntsuam tau ua rau L6000 database. Cov txheej txheem tshwj xeeb tau qhia hauv daim duab 2. Tom qab Highput virtual screen, thiab ultra-precision virtual qhab nia yog -1}, qis dua -13.009 kcal / mol, thiab nruab nrab yog -14.396 kcal / mol. Qhov 100 khaws cov ntawv sib txuas tau rov ua tau cov qhab nia siv hli-GBSA, thiab 49 cov tebchaw tau thaum kawg tau txais thaum kawg. Tom qab clustering thiab conformational kev tsom xam, thiab lub npe sib txuas nrog thawj cov neeg sib tw me me, raws li cov neeg sib tw sib txuas, raws li qhia hauv Table 1 thiab Daim Duab 3.

Daim duab 1 schematic daim duab ntawm cetp protein khi hnab ris (a), schematic daim duab ntawm cetp protein binding site (b)

Daim duab 2 Flow cov ntawv kos ntawm virtual tshuaj ntsuam thiab molecular dynamics simulation

 

2.3 Kev Tshawb Xyuas Sawv Cev

Tom qab clustering tsom xam raws li qhov sib thooj ntawm 19 lub tebchaw thiab cov crystallized ligandized ligandized ntawm 3 pawg raws li kev sib tshooj ntawm kev sib tshooj ntawm cov qauv molecular. Daim duab 4a qhia thawj pawg, uas muaj 14 me me molecules, qhia tias cov pob txha ntawm cov molecules feem ntau yog qhov zoo sib xws; Daim duab 4B qhia tus cluster thib ob, uas muaj 1 me molecule, thiab daim duab 4C qhia tau tus pawg thib peb, uas muaj 4 molecules me me. Cov xim dub nyob hauv daim duab yog cov taum tau muaj tseeb, thiab tus so yog cov lwg me me tau los ntawm kev kuaj xyuas virtual.

2.4 khi hom tsom

Los ntawm kev txiav txim siab txiav txim siab cov qhab nia sib tw thiab siv lub zog sib tw dawb ntawm 19 lub tebchaw tau raug xaiv rau kev tshawb xyuas hom kev tshawb xyuas hom, suav nrogcistanche glycoside a, theflavins, thiab salvianic acid b dimethyl eser. Txoj kev khi hlua hom daim duab ntawm peb qhov sib txuas no thiab cetp protein protein tau kos siv pymol software. Qhov kev sib cuam tshuam ntawm cov amino acid residues ntawm peb linands thiab lub hom phiaj protein tau txhawb nqa cov protein-ligand complex, ua rau nws ruaj khov ua ke.
Ntawm lawv,Contancheside aUa ib qho kev sib tw hydrogent hydrogen nrog Phe463 ntawm lub hom phiaj protein, thiab ua cov kev sib tw hydrogen ntau nrog Phe263; Cov ntaub ntawv hauv lub caj pas tam sim no cov hom phiaj hydrogen sib txuas, ua cov phiaj xwm hydrogen pitter nrog Phe263, thiab ua cov kev sib cuam tshuam nrog Phe461; Dimethyl Ester ntawm Salvianic Acid B cov kua txiv uas muaj ntxhiab Hydresic Hydrogen Bonds nrog HER232 thiab cov hom phiaj muaj protein, thiab cov ntawv sib txawv ntawm Phe463. Lwm qhov kev sib cuam tshuam txog cov protein xws li kev sib cuam tshuam hydrophobic thiab cov ntsev tau tshwm sim hauv daim duab 5.

2.5 molecular dynamics simulation

2.5.1 rmsd nqi xam xam

 

Raws li qhia hauv daim duab 6A, tom qab simulation ntawm lubContancheside A-Cetp systemRau 1 0 ns, Rmsd Friblicate ntau yog ruaj khov hauv qab no. 1 N}}. 1 N}}. 1 N}}. 1 N}}. 1 N}}. 1 N}}. Tom qab 25 ns ntawm simulation, kev hloov pauv ntawm The Asflavin-Cetp pib ua kom qeeb li ntau, thiab kev hloov pauv hauv qab no {9}}. 1 nm, ncav tes sib npaug; Tus lej RMSD tus nqi ntawm tannic acid breatethyl-cet tau hloov pauv tsawg dua tom qab 0.1 nm, mus txog equilibrium. Ib qho ntxiv, txoj kev tshawb no tseem tau suav cov RMSD tus nqi ntawm lub lasig.
Raws li tuaj yeem pom los ntawm daim duab, tus the -flavin-cetp yog nyob rau hauv lub xeev ruaj khov nyob rau theem pib ntawm lub simulation, thaum lubcistance a-cetpThiab cov tannic acid b dimethyl eser-cet kho kom ruaj khov tom qab lub sijhawm sai sai. Qhov sib txawv no tej zaum yuav tshwm sim los ntawm kev teeb tsa molecular sib txawv thiab qhov sib txawv ntawm cov rog sib cuam tshuam hauv cov kab noj hniav. Peb feem ntau nyob hauv kev sib npaug.

 

2.5.2 RMSF tus nqi xam raws cov txheej txheem nyuaj ntawm cov tshuaj sib txawv thiab cetp

Cov protein, txoj kev kawm no tau xam cov RMSF tus nqi ntawm cov protein amino acid seem ntawm txhua pawg. Raws li tuaj yeem pom los ntawm daim duab 6B, RMSF qhov tseem ceeb ntawm lub cetp yog qhov muaj txiaj ntsig me me ntawm {}. 16 n}}. 16 n}}. 16 n}}. khi ntawm lub lasig thiab cov protein.

 

2.5.3 SASA NQI TXHEEJ TXHEEM

Raws li tuaj yeem pom los ntawm daim duab 6c, SASA ntawm ob txoj kev sib txawv ntawm cov kab mob proteined ntawm cov kev ua kom sai, thiab thaj tsam ntawm cov tshuaj protein ntau vim yog cov kev coj tsis zoo vim yog tus cwj pwm khi. Qhov txo qis hauv Sasa tuaj yeem ua rau pom tias lub ligndly tau khi rau cov protein ntau rau cov protein, thiab tuaj yeem nrog kev hloov pauv ntawm cov protein. Raws li cov simulation txuas ntxiv, vim yog cov kev dov ntawm cov protein ntawm cov protein ntawm cov simulation, thiab nws yog kev kwv yees ntawm ob qho tsis muaj zog ntawm theem no. Qhov no yuav yog vim muaj kev poob qis stagab poob peev los ntawm cov protein conformations kev ntxhov siab. Tom qab ntawd, Sasa nkag rau theem peb thiab txo qis kom sai kom txog thaum kawg ntawm kev sim. Lub Sasa ntawm lub complex ntawm Salvianic Acid B Cheerethyl-Cetp txo thoob plaws lub xeev thiab nkag mus rau lub xeev ruaj khov tom qab 40 ns.

 

2.5.4 Cov qauv kev tawm tswv yim theem nrab

Raws li pom hauv daim duab 7, lub -helix cov ntsiab lus sib piv ntawm cov protein hauv peb pawg ntawm cov nyom yog qhov nce ntxiv, thiab tsis pom tseeb lossis txo qis yog pom. Hauv custaneside A-Cetp, nws tuaj yeem pom meej meej cov ntsiab lus txo thiab cov kauj ruam} NS, thiab nce thiab txo cov kev hloov pauv tom qab 25 NS. Nyob rau hauv theflavin-cetp, nws tuaj yeem pom tau tias qhov hloov tau hloov ntau feem ntau tshwm sim hauv kev sib hloov pauv hloov dua tshiab ntawm -til. Nyob rau hauv tannic acid b dimethyl eser eser-cetp, qhov kev hloov pauv tseem ceeb yog qhov txo qis thiab nce ntawm chev. Cov kev hloov ntawm cov protein theem nrab cov ntsiab lus yog cuam tshuam los ntawm cov amino acids nyob ze ntawm lub vev xaib. Vim muaj cov haujlwm sib txawv ntawm Ligand molecules hauv cov nyom sib txawv thiab cov hom sib txawv, cov protein ntau ntawm txhua pawg kuj txawv. Feem ntau, cov ntsiab lus ntawm cov qauv protein theem hauv txhua pawg tau pom tseeb txog kev nruj me ntsis ntawm lub ligand.

 

3 kev sib tham

Ntshav lipids yog ib lo lus dav dav rau nruab nrab rog thiab lipids hauv ntshav. Qhov sib npaug ntawmCov ntshav lipol metabolismyog qhov tseem ceeb los tswj txoj kev ua lub neej ntawm cov hlwb thiab cov kab mob; Cov ntshav metabolal txawv txav yog qhov tshwm sim ntawm cov kev tshwm sim ntawm cov kab mob plawv thiab cov kab mob cerebrovases thiab qog ntshav thiab qog [{0}}]. Kev lees paub thiab kev kho mob ntawm dyslipidemia hauv cov tshuaj suav suav hauv ib txwm muaj. Tsoos suav tshuaj muaj qhov zoo ntawm cov kev nplua nuj, cov qauv sib txawv, ob peb yam tsis zoo thiab cov nqi qis. Nws muaj qhov cuam tshuam zoo nyob rau hauv kev tswj cov Lipid kev txawv txav thiab tau pom dav dav hauv kev tshawb fawb thiab cov ntawv thov kev kuaj mob hauv tsev thiab txawv teb chaws [{1}}].
Kuaj cov molecules me me ntawm cov tshuaj ntsuab kev tshuaj ntsuab uas tuaj yeem siv rau kev cai thiabKev Kho Mob ntawm DyslipidemiaLos ntawm high-aws exputure Suav tshuaj Monomer database yog ntawm kev siv tswv yim tseem ceeb. Kev soj ntsuam virtualing thev naus laus zis thiab molecular dynamics Simulation Technology thiab txhais tau tias nyob rau hauv cov cuab yeej tseem ceeb tshaj plaws, thiab tuaj yeem tshawb xyuas cov molecules tam sim no ntawm lub ntsuas loj [17]. CETP yog ib qho tseem ceeb tswj hwm enzyme koom nrog lipid metabolism thiab tus txheej txheem hauv cov ntshav ncig. Txoj kev tshawb no tsom rau kev ua haujlwm thiab lub luag haujlwm ntawm cetp protein. Los ntawm virtual tshuaj xyuas kev tshawb fawb, 19 tus neeg sib tw uas yog kev sib tw nrog kev muaj affinity rau cetp protein tau txais. Backebo rangority ntawm tus neeg sib tw yog kev qhia los ntawm pawg tsom xam, thiab sab saum toj 3 ligtand me me molecules tau xaiv rau kev tshawb xyuas hom hom. Lub hydrophobic sib cuam tshuam, π-π-π-Π cov choj thiab rov qab ua lub luag haujlwm tseem ceeb hauv kev tswj hwm qhov muaj zog muaj zog ntawm cov protein ligand. Txoj kev kawm no tseem tau tshawb txog kev ruaj ntseg ntawm 3 tus neeg sib cav sib tw protein-liigand complexes los ntawm MD simulation. Cov txiaj ntsig tau pom tias RMSD, RMSF thiab SASA graphs ntawm sab saum toj 3 protein-liigand compendation tom qab hloov pauv tau me me yog me me. Qhov pom tseeb hloov hauv cov qauv theem nrab ntawm cov protein kuj tau qhia txog txoj kev kaw ntawm cov protein ligand. Yog li ntawd, lawv tau txiav txim siab ua kom cov neeg sib tw rau cov molecule me me uas muaj kev sib raug zoo rau cetp protein.

 

 

Cistance a yog cov phenylethanol glycoside compound, uas yog feem ntau pom nyob rau hauv cov tshuaj suav suav xws li contanche thiab Rehmannia. Nws cov feem ntau feem hauv cistance yog {{{{{{} {{}}}. 07%, uas yog ib txoj kab sib dhos [18].

Shimoda li al. [19] Tshaj tawm tias cistanche extract tuaj yeem nthuav tawm cov kev ntsuas ntawm cov roj Irterol thiab cov tshuaj metabolism ntsig txog kev noj haus cov nas thiab qhia cov roj cholesterol. TheSeflavins yog cov khoom sib txawv tsim thaum lub sijhawm fermentation txheej txheem ntawm cov tshuaj yej dub, thiab lawv cov ntsiab lus hauv cov tshuaj yej dub, thiab}. 5% ntawm cov khib nyiab [20]. Kev tshawb fawb tswj hwm tau pom tias tshuaj yej extractins nplua nuj nyob rau hauv cov zaub mov muaj roj thiab muaj peev xwm txo qis cov neeg laus uas muaj kev kub ntxhov ntawm hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes nrog hypercholes [21]. Salvianic Acid B CheTethyl Ester yog cov muaj roj ua kom zoo nkauj ntawm cov hauv paus hniav roj actethyl yog nyob rau hauv lub hauv paus ntawm Salvia miltiorrhiza [22]. Cov kev tshawb fawb yav dhau los tau qhia tias Salvianic Acid B CheTethyl cov kev ua haujlwm tau zoo sib xws li salvianic acid b [22-23]. Yog li ntawd, lub ntuj me me molecule compound cistanche Squaticola A, Refirectiver accompent hauv txoj kev kho mob Suav teb tsis tau los ntawm kev kho mob molecular, Pab ntsuas cov khoom siv hauv cov khoom siv cov khoom siv tseem ceeb, ua ke thiab pom cov tshuaj lom neeg hauv cov tshuaj ib txwm muaj los tsim cov tshuaj suav ib txwm muaj. Ib qho ntxiv, lwm lub cetp protein inhibitors xws li isofuspastoside, xws li suav cov tshuaj hauv cov tshuaj tiv thaiv kab mob hauv lub ntsej muag, thiab lub sijhawm, tuaj yeem kawm tau ntxiv thiab paub tseeb hauv kev tshawb fawb yav tom ntej.