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mang li hiu qu khng nh cho ngnh cng nghip ha dc, tuy nhin vn cn nhiu yu tcn phi hon thin trong qu trnh ng dng vo thc tin. Trong bi bo ny, da trn c s

nhng thuc chng st rt bit, chng ti la chn Artemisinin v cc hp cht c cu trctng t artemisinin nghin cu cu trc v hot tnh o ca chng s dng phn mm mphng docking. Cc kt qu thu c rt c tim nng, chng ch ra mi tng quan tt giahot tnh chng st rt thc nghim v hot tnh chng st rt o i vi ch sinh hc nghincu. T cc kt qu nghin cu, chng ti cng xut s dng phng php m phng dockingny nghin cu sng lc cc loi thuc mi chng li cc bnh truyn nhim v mt s bnhnan y khc.

Keywords: Malaria, molecular docking, virtual screening.

I - GII THIU

Bnh St rt (SR) l mt bnh truynnhim do k sinh trng trong mu Plasmodiumsp. gy ra, thng gp cc nc nhit i.Bnh ly lan ch yu t ngi ny sang ngikhc qua trung gian l mui n xc (mui

Anopheles). K sinh trng st rt (KSTSR) sngch yu trong hng cu mu v gy bnh tonthn. Biu hin in hnh thng l cn st rt,c km gan, lch ln hoc thiu mu, nng cth gy t vong. Bnh thng gp cc ncang pht trin, hng nm c ti trn 300 triutrng hp mc st rt, trong 1-1,5 triu

bnh nhn t vong [1,2].Cc loi thuc chng st rt th h trc

nh DHA, cloroquine thng vp phi vn khng thuc, trong khi vic pht trin ccloi thuc mi thng rt tn km v mt nhiuthi gian. Cho n hin nay th cng cha cvaccine phng nga bnh st rt [3,4].

Trong c ch gy bnh ca cc k sinhtrng Plasmodium, qu trnh chuyn hahemoglobin ng mt vai tr ht sc quantrng. Qu trnh ny quyt nh s sng st v

pht trin ca k sinh trng trong trong c thngi. Cho ti nay, cc nh khoa hc tm ramt s protein c lin quan n qu trnh phnhy ca cc hemoglobin hng cu bn trong cckhng bo ca k sinh trng, trong

plasmepsin l mt nhm cc aspartic proteinquan trng nht ca Plasmodium. C tt c 10

plasmepsin khc nhau c m ha bi 10 genkhc nhau trong Plasmodium sp.(Plm I, II, IV,V, VI, VII, VIII, IX, X v HAP). Cu trc ca

cc plasmepsin ny c xc nh kh r

rng nh cc d liu nhiu x tia X [5,6].Trong tt c cc plasmepsin th plasmepsin

II l protein quan trng nht v cng cnghin cu nhiu nht. Chnh v vy, chng ti la chn plasmepsin II lm ch sinh hc chovic sng lc o cc loi thuc chng st rt thh mi s dng phng php m phngdocking.

nh gi s ph hp ca phng phpm phng docking, chng ti s dng c s dliu cc hp cht dn xut ca artemisinin vcc hp cht c cu trc tng t. Cu trc 3Dca cc hp cht ny c thit lp s dng cc

phn mm ha tin di dng file mol2. Gi trhot tnh chng st rt ca chng thu c tcc thc nghim v t cc ti liu tham kho[8].

II - VT LIU V PHNG PHPLa chn protein ch: y chng ti

la chn protein plasmepsin II, c m s trnProtein Data Bank l 1lee (hnh 1), protein nyc nghin cu v cu trc 3D ca n c

thit lp bi phng php nhiu x tia X. Trongtrung tm hot ng ca 1lee c cha cht cch i cng l R36. y l d kin quan trng xc nh tm hot ng ca 1lee.

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Hnh 01: cu trc 3D ca 1lee v cc tng tcca n vi cht c ch R36

Chun b protein ch: Cu trc 3D caprotein thu c t c s d liu PDB. Ccphn t nc v cht c ch R36 c loi bkhi protein trc khi thc hin m phng

docking. V tr tm hot ng ca 1lee c chotrng vi v tr tm ca cht c ch R36 c bnknh khong 6,5 Ao. in tch ca cc aminoaxit nh lysine, histidin v arginin c gn

bng +1, in tch ca cc nhm cacboxyl caaxit glutamic v axit aspartic c gn bng 0(ph hp vi cc tnh ton t AutoDock). Mtvi thng s nh kch thc hp th, bc quayt do c thay i cho ph hp, cc thngs khc c gi nguyn [7].

M t trung tm hot ng ca protein1lee: Trung tm hot ng ca protein ng vai

tr v cng quan trng i vi cc m phngdocking. Trung tm hot ng cung cp ccthng tin v phng thc lin kt ca proteinvi cht c ch cng nh nhng amino axittham gia trc tip vo qu trnh tng tc

protein-cht c ch ny. i vi trng hp ca1lee th cc animo axit tham gia vo tng tcln lt l Val78, Ser79, Asp34, Asp214,Ser218 v Gly36 nm gn khu vc trung tmhot ng. Cc tng tc ca protein vi chtc ch R36 c cho trong hnh 02.

Hnh 02: Cc tng tc gia protein v cht cch R36 trong trung tm hot ng ca protein

La chn c s d liu cc cht c ch:

nh gi s ph hp ca phng php mphng docking s dng AutoDock, c s dliu c la chn l artemisinin v cc dnxut ca n. Cc hp cht ban c chun bcng thc cu trc 3D di dng file mol2, sau c chuyn thnh cc file pdpqt tngthch vi c s d liu u vo ca AutoDock.Hot tnh chng st rt ca cc hp cht nghincu c thc hin trn k sinh trng

Plasmodium falciparum.M phng Docking: Cc tnh ton m

phng docking c thc hin s dng cng cAutoDock 4.2 v giao din AutoDockTools.AutoDock l mt cng c tnh ton m phngdocking t ng. Cc thut ton c la chnl Lamarckian genetic algoriths (LAG) [7].

Phn tch kt qu sau docking: Cc chtc ch nghin cu c xp xp theo th t vgi tr nng lng lin kt (Ebinding) gia proteinv cht c ch. Ngoi ra cng nghin cu v trca cht c ch bn trong phn t protein vnhng tng tc c th ca chng vi protein.Tt c cc nghin cu ny thc hin trn cc

tin ch i km vi b phn mm AutoDock.KT QU V THO LUN

Hot tnh chng st rt ca cc hp chtnghin cu: Cc dn xut ca artemisinin uth hin kh nng c ch k sinh trng P.

falciparum kh tt. Cc s liu c trnh bytrong bng 01.Bng 01:Hot tnh chng st rt IC50 ca cc

hp cht nghin cu

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Artemisinin Dn xut caArtemisinin

STT Hp cht R IC50(M)1 HC1 -H () 0,832 HC2 -H () 12,593 HC3 -CH3 () 13,97

4 HC4 -CH3 () 10,95 HC5 -C2H5 () 6,726 HC6 -n-C3H7 () 25,797 HC7 -n-C3H7 () 7,728 HC8 -CH2CH2CH(CH3)2 () 19,489 HC9 -CH2CH2OCH3 () 14,1410 HC10 -CH2CH2OCH2CH2CH3 () 12,7911 HC11 -CH2CH2COCH3 () 25,0012 HC12 -COCH3 () 4,1413 HC13 -COC2H5 () 22,8314 HC14 -COC3H7 () 28,5915 HC15 -COOC2H5 () 23,97

16 HC16 -COOC3H7 () 52,6217 HC17 -CO(p-CH3)C6H4 () 5,9718 HC18 -COCH=CHC6H5 () 2,5519 HC19 -COC6H5 () 4,4520 HC20 -COOC3H7 () 21,6621 HC21 -COOC6H5 () 2,1722 HC22 -COOCH2C6H5 () 3,28

Da vo bng gi tr IC50, thy rng HC1l hp cht c ch tt nht i vi protein 1lee.Trong khi th cc hp cht cha cc nhmth ln hn th li th hin kh nng c ch kmhn. iu ny l hon ton ph hp do cc phnt ln, cng knh s lm gim tnh tan ca chtc ch, do cng lm gim hot tnh ca n.

Nng lng lin kt v hng s c ch:Nng lng lin kt (Ebinding) gia th th v chtc ch c cho trong bng 03. Cc gi tr nyny m t nng lng gii phng trong qu trnhcht c ch tng tc vi th th c tnhthng qua mt s nng lng khc ca phn t(bng 02). Tng t, chng ti cng thu cgi tr IC50 l thuyt thng qua cc tnh ton sdng phn mm AutoDock. y l nhng gi trtnh ton l thuyt c tnh ton thng quathut ton Lamarckian genetic algoriths.

Bng 02: M t tnh ton nng lng lin kt v hng s c ch thng qua phng php m phngdocking s dng Autodock4

Bng 03: Gi tr nng lng lin kt v hng sc ch ca cc hp cht nghin cu

STT Hp cht Ebinding(kcal/mol) Ki (M)1 HC1 -7,26 4,762 HC2 -7,35 4,133 HC3 -7,0 7,434 HC4 -7,20 5,305 HC5 -7,10 6,246 HC6 -6,68 12,687 HC7 -6,97 7,88 HC8 -6,98 7,639 HC9 -6,62 14,1210 HC10 -6,37 21,48

11 HC11 -6,54 16,03

12 HC12 -7,12 6,0513 HC13 -6,88 9,1114 HC14 -6,34 22,4715 HC15 -6,51 17,0316 HC16 -5,97 41,917 HC17 -7,74 2,1218 HC18 -7,99 1,3919 HC19 -7,77 2,0220 HC20 -6,61 14,3821 HC21 -7,41 3,6822 HC22 -8,12 1,11

Nng lng lin kt tnh ton = - 6.62 kcal/mol [= (1) + (2) + (3) (4)]

Hng s c ch tnh ton, Ki = 14.12 M vi T = 298.15KTrong : (1) l tng nng lng tng tc (NLTT) phn t = - 7.81 kcal/mol

(1) = NLTTvanderwaal + NLTThydro + NLTTdesolvat ha + NLTTtnh inNLTTvanderwaal + NLTThydro + NLTTdesolvat ha = - 7.79 kcal/mol

NLTTtnh in = - 0.02 kcal/mol(2) l ni nng ton phn = - 0.60 kcal/mol(3) l nng lng xon t do = 1.19 kcal/mol(4) l nng lng ca h cha lin kt [=(2)] = - 0.60 kcal/mol

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