Bước đầu xây dựng cơ sở dữ liệu các hợp chất thiên nhiên Việt Nam phục vụ cho việc sàng lọc ảo

Header Page of 116 I HC QUC GIA H NI KHOA Y DC NGUYN TH THU H BC U XY DNG C S D LIU CC HP CHT THIấN NHIấN VIT NAM PHC V CHO VIC SNG LC O KHểA LUN TT NGHIP DC S I HC H Ni 2017 Footer Page of 116 Header Page of 116 I HC QUC GIA H NI KHOA Y DC NGUYN TH THU H BC U XY DNG C S D LIU CC HP CHT THIấN NHIấN VIT NAM PHC V CHO VIC SNG LC O KHểA LUN TT NGHIP DC S I HC Khúa: QH.2012.Y Ngi hng dn: TS Lờ Th Thu Hng PGS.TS Dng Th Ly Hng H Ni 2017 Footer Page of 116 Header Page of 116 LI CM N Lun ny c thc hin ti B mụn Dc liu Dc hc c truyn, Khoa Y-Dc, i hc Quc gia H Ni Tụi xin by t lũng kớnh trng v bit n sõu sc ti TS Lờ Th Thu Hng, ging viờn B mụn Dc liu Dc hc c truyn; PGS.TS Dng Th Ly Hng, ging viờn B mụn Dc lý - Dc lõm sng, Khoa Y-Dc, i hc Quc gia H Ni ó giao ti v luụn bờn tụi sut quỏ trỡnh lm lun vn, ch bo tụi v chuyờn mụn cng nh ng viờn tụi cuc sng, giỳp tụi hon thnh tt ti nghiờn cu Tụi xin chõn thnh cm n TS ng Thanh Hi, ging viờn Khoa Cụng ngh thụng tin, trng i hc Cụng ngh, i hc Quc gia H Ni ó giỳp tụi a CSDL giao din web Bờn cnh ú tụi xin gi li n ti ban qun lý th vin Quc gia, th vin i hc Dc H Ni, th vin Vin hn lõm Khoa hc Cụng ngh, Dc hc cỏc nh sỏng lp v qun lý ca ChemAxon, ChemMine Tools, ClassyFire - The Metabolomics Innovation Centre (TMIC) ó tn tỡnh giỳp tụi sut thi gian thc hin lun Cui cựng, xin by t lũng bit n sõu sc nht ti gia ỡnh, ngi thõn v bn bố l nhng ngi ó luụn quan tõm, chm súc v ng viờn tụi sut thi gian hc v lm vic Xin trõn trng cm n! H ni, ngy thỏng nm Sinh viờn Footer Page of 116 Header Page of 116 DANH MC CC K HIU, CH VIT TT Ký hiu Din gii CSDL C s d liu YHCT Y hc c truyn FDA Food and Drug Administration (Cc qun lý thuc v thc phm M) IUPAC International Union of Pure and Applied Chemistry (Liờn minh Quc t v Húa hc thun tỳy v Húa hc ng dng) NIST National Institute of Standards and Technology (Vin Tiờu chun v Cụng ngh M) SMILES Simplified Molecular Identification and Line Entry System (H thng n gin húa vi u vo di dng dũng biu din phõn t) InChi IUPAC International Chemical Identifier (Nhn dng húa hc quc t theo IUPAC) InChiKey IUPAC International Chemical Identifier Key (Dng rỳt gn ca nhn dng húa hc quc t theo IUPAC) MACCS Molecular ACCess System (H thng truy cp phõn t) NCI National Cancer Institute (Vin ung th quc gia M) VNPD_ID Vietnam Natural Products Database _Identification (nh danh ca hp cht c s d liu cỏc hp cht t nhiờn Vit Nam) Footer Page of 116 Header Page of 116 MC LC DANH MC CC K HIU, CH VIT TT DANH MC CC BNG DANH MC CC HèNH V, TH T VN CHNG TNG QUAN TI LIU 1.1 Nghiờn cu cỏc hp cht thiờn nhiờn 1.1.1 Vai trũ hp cht thiờn nhiờn quỏ trỡnh nghiờn cu v phỏt trin thuc hin i 1.1.2 Y hc c truyn .4 1.1.3 Tng quan v quỏ trỡnh nghiờn cu phỏt trin thuc mi 1.2 Tng quan v CSDL cỏc hp cht cú ngun gc t nhiờn 1.2.1 Trờn th gii 1.2.2 Ti Vit Nam 1.3 C s d liu cỏc hp cht 1.3.1 Biu din v nhn dng cỏc hp cht húa hc bi mỏy tớnh 1.3.2 Thụng tin liờn quan v hp cht c phõn lp 11 1.3.3 Cỏc c tớnh vt lý v húa hoc ca hp cht 11 1.4 Khai thỏc CSDL 11 1.4.1 S dng CSDL 12 1.4.2 ng dng CSDL cho quỏ trỡnh sng lc o in silico 12 1.4.3 Xõy dng cỏc h thng xỏc nh mc tiờu phõn t ca cỏc hp cht 13 CHNG I TNG V PHNG PHP NGHIấN CU 14 2.1 i tng nghiờn cu 14 2.2 Phng phỏp, thit b nghiờn cu 14 2.2.1 Phng phỏp thu thp s liu 14 2.2.2 Phng phỏp x lý s liu 14 2.2.3 Thit lp giao din website 17 2.2.4 Thit b nghiờn cu 19 CHNG KT QU V THO LUN 20 3.1 Ni dung CSDL cỏc hp cht cú ngun gc thiờn nhiờn Vit Nam 20 3.1.1 S lng cỏc hp cht 20 3.1.2 Phõn loi cỏc hp cht theo c im cu trỳc húa hc 20 Footer Page of 116 Header Page of 116 3.1.3 Phõn loi cỏc hp cht theo nhúm tỏc dng sinh hc 27 3.1.4 ỏnh giỏ mc ging thuc theo quy tc s ca Lipinski 30 3.2 VNPD website 31 KT LUN V KIN NGH 35 Ti liu tham kho Ph lc Ph lc Ph lc Ph lc Ph lc Footer Page of 116 Header Page of 116 DANH MC CC BNG Bng 1.1 Tờn bng Trang Mt s CSDL cụng cng cú cha cỏc hp cht cú ngun gc thiờn nhiờn 1.2 Mt s CSDL v hp cht cú ngun gc t nhiờn trờn th gii 3.1 Thng kờ cỏc phõn nhúm chớnh CSDL 21 3.2 S vi phm quy tc Lipinski ca cỏc hp cht CSDL 30 Footer Page of 116 Header Page of 116 DANH MC CC HèNH V, TH Hỡnh Tờn hỡnh Trang 1.1 Quỏ trỡnh nghiờn cu v phỏt trin thuc mi 2.1 CSDL ban u vi cỏc thụng tin c thu thp v trỡnh by trờn Exel 15 2.2 Mụ t ni dung v cỏc trng ln ca CSDL 17 2.3 Quỏ trỡnh a d liu hin th cho thụng tin truy 18 3.1 Biu biu th s phõn b ca cỏc nhúm phõn loi chớnh ca cỏc hp cht CSDL 22 3.2 Cỏc biu biu th s phõn b cỏc phõn nhúm nh ca mt s nhúm chớnh CSDL hin cú 25 3.3 Thng kờ tỏc dng dõn gian ca cỏc hp cht ghi nhn c CSDL 28 3.4 Thng kờ tỏc dng dc lý ó c chng minh ca cỏc hp cht ghi nhn c CSDL 29 3.5 Cỏc biu biu th s ỏnh giỏ cỏc hp cht CSDL da theo quy tc s ca Lipinski 30 3.6 Giao din VNPD cung cp cỏc thụng tin v hp cht Barlupulin A 32 3.7 Kt qu tỡm kim sterol trng Tờn thụng thng VNPD 33 3.8 Footer Page of 116 Kt qu tỡm kim Xoan rng trng Ngun phõn lp VNPD 33 Header Page of 116 T VN Thuc cú ngun gc t nhiờn úng gúp mt phn quan trng h thng chm súc sc khe trờn ton th gii Theo c tớnh ca t chc Y t Th gii (WHO), 80% dõn s trờn ton th gii s dng thuc cú ngun gc t nhiờn nh mt la chn hng u vic phũng v cha bnh Gn õy, xu hng ton cu ca vic s dng cỏc sn phm t nhiờn phũng nga v iu tr cỏc bnh v th cht v tinh thn, tho dc ngy cng c chỳ ý cỏc iu tri lõm sng trờn ton th gii Trong k nguyờn thng tr ca húa hc t hp hin i, ngi ta cú th s dng phng phỏp tng hp, bỏn tng hp to cỏc phõn t mi, thit k cỏc cu trỳc thuc mi Nhng theo mt s nghiờn cu ó c cụng b, cỏc hp cht cú ngun gc t nhiờn cú cỏc c tớnh húa hc ging thuc hn so vi cỏc hp cht tng hp c t húa t hp [41] tng hp mt s lng ln cỏc d liu húa sinh v rỳt ngn thi gian phỏt minh thuc mi, cỏc CSDL phõn t ó c xõy dng v tr thnh mt cụng c hu ớch cho cỏc nh thit k thuc Trong s ú, CSDL cu trỳc ca cỏc hp cht c phõn lp t tho dc t nhiờn mang li nhiu ng dng hiu qu thc t, cỏc tho dc t nhiờn cú th c xem nh l mt ngun phong phỳ v tim nng, l cỏc ng viờn lm thuc [20] Khoa hc hin i giỳp chỳng ta cú th phõn tớch sõu hn v dc liu, t cỏc thnh phn húa hc cu thnh n cỏc tỏc dng dc lý liờn quan qua nhng nghiờn cu thc nghim Hng nm cú rt nhiu bỏo cỏo v phõn lp v chit tỏch cỏc thnh phn húa hc ca cõy c cụng b trờn cỏc khoa hc quy mụ quc gia, quy mụ quc t Nhng cỏc bỏo cỏo ny ch dng li mc cụng b m cha thc s em li c mt giỏ tr thc tin Cỏc bỏo cỏo cung cp cho chỳng ta nhng thụng tin tng i y v ỏng tin cy v cỏc hp cht húa hc c phõn lp t cõy tho dc vi cu trỳc húa hc, nh danh, tỏc dng dõn gian, tỏc dng dc lý ó c chng minh, ngun dc liu lm thớ nghim Mc dự ta cú c mt lng thụng tin ln v a dng v cỏc hp cht, nhng ch cú mt t l nh s a dng ú c khai thỏc nghiờm tỳc cho tim nng dc lý ca nú Nhng thụng tin ny ó c nghiờn cu v cụng b rng rói nhng cha cú mt s quy t hay qun lý chung, l mt khú khn cụng tỏc tỡm kim v chn la i vi cỏc nh khoa hc Do vy, vic a cỏc gii phỏp thu thp v qun lý mt cỏch hiu qu l rt cn thit hin nay, c bit l nhng xut, gii phỏp mang tớnh cụng ngh ng dng i vi qun lý hiu qu Footer Page of 116 Header Page 10 of 116 thỡ vic xut cỏc gii phỏp ng dng cụng ngh thụng tin vo xõy dng CSDL v h thng phn mm giỳp cho vic thu thp, qun lý v tra cu l ht sc cn thit Trờn th gii, mt s quc gia phỏt trin nh Trung Quc, Nam Phi, Brasil ó xõy dng thnh cụng h CSDL v cỏc hp cht phõn lp t tho dc thiờn nhiờn t nc h [1, 8, 22] V ó cú mt s bỏo cỏo ghi nhn cỏc trng hp thit k thuc thnh cụng da trờn cỏc tỡm kim CSDL cu trỳc ú Ngy nay, vic tỡm kim cỏc hot cht t nhiờn cú hot tớnh sinh hc cao lm thuc l mt xu th c rt nhiu cỏc nh khoa hc quan tõm Vit Nam l mt nhng quc gia thuc cỏc vựng nhit i ni cha ng giỏ tr a dng sinh hc cao cha c khỏm phỏ, õy nh l mt tim nng v cng l mt thỏch thc ln cho vic xõy dng v khai thỏc CSDL mt cỏch ti u nht Do ú, chỳng tụi tin hnh ti: Bc u xõy dng c s d liu cỏc hp cht thiờn nhiờn Vit Nam phc v cho vic sng lc o vi cỏc mc tiờu chớnh sau: - Xõy dng c mt CSDL gm cỏc hp cht cú ngun gc thiờn nhiờn Vit Nam Xõy dng mt giao din website qun lý v s dng CSDL hiu qu Footer Page 10 of 116 Header Page 40 of 116 Hỡnh 3.6: Giao din VNPD cung cp cỏc thụng tin v hp cht Barlupulin A VNPD_ID l nh danh nh qun lý t cho cỏc hp cht CSDL, mi hp cht s cú mt ID nht Cỏc thụng tin v hp cht a gm: Cụng thc; Hỡnh nh biu din cu trỳc nh dng 2D; Tờn thụng thng; Tờn IUPAC; SMILES; InChi; InChiKey; Phõn nhúm cu trỳc; Cỏc thụng s húa hc c trng (Khi lng phõn t, XlogP, S liờn kt cho Hydro, S liờn kt nhn Hydro, S vi phm quy tc s ca Lipinski, s liờn kt xoay ng v); Thụng tin v ngun phõn lp (Tờn thc vt, Tờn khoa hc, H, a im thu hỏi mu, Thi gian ly mu, B phn dựng, Tỏc dng dõn gian, Tỏc dng dc lý ó c chng minh); Ti liu tham kho VNPD cung cp cho ngi s dng giao hin i vi 10 trng tỡm kim d liu bao gm: VNPD_ID; Cu trỳc; Tờn thụng thng; SMILES; Nhúm chớnh; Ngun phõn lp; H; a im thu hỏi mu; B phn dựng; Ti liu tham kho Khi ngi tng tỏc nhp thụng tin cn tỡm vo mt 10 Footer Page 40 of 116 Header Page 41 of 116 trng vi d liu phự hp, CSDL s a mt danh sỏch cỏc d liu cú kt qu tng ng v liờn quan nh Hỡnh 3.7 v Hỡnh 3.8 Hỡnh 3.7: Kt qu tỡm kim sterol trng Tờn thụng thng VNPD Hỡnh 3.8: Kt qu tỡm kim Xoan rng trng Ngun phõn lp VNPD Sau h thng phõn tớch v lc thụng tin, giao din s a mt danh sỏch cỏc kt qu Trong VNPD, mt hp cht cú th c thu thp t nhiu ngun phõn lp khỏc v c truy vn, thụng tin v cỏc ngun ny s c hin th y nh vi hp cht Daucosterol cú th c phõn lp t nhiu ngun dc liu khỏc (bch ng n, gin sng, bự d hoa , nit giú, ct khớ, da cn, n kim, mt nhõn) i kốm vi thụng tin c bn ban u c hin th (VNPD_ID, cu trỳc, tờn thụng thng, ngun phõn lp) mi hp cht c dn link n mc qun lý y thụng tin v hp cht ú nh Hỡnh 3.6 (VNPD_ID l ng link) Vi Footer Page 41 of 116 Header Page 42 of 116 trng Ngun phõn lp, ta cú th tỡm kim bng cỏch gừ tờn thụng thng hay danh phỏp khoa hc ca cõy ú; v giao din s a cỏc hp cht ó c phõn lp t ngun ú Vi cỏc trng tỡm kim khỏc cng tng t (chỳ ý ni dung tỡm kim phi phự hp vi nh dng tỡm kim ca tng trng) Tuy cha a c CSDL lờn giao din v s dng nh mt web online, nhng v mt ni dung v hỡnh thc, VNPD tng i hon thin so vi nhng CSDL v cỏc hp cht thiờn nhiờn trờn th gii õy l mt h thng d liu c xõy dng t cht liu Vit mang nhng nột c trng riờng ca thiờn nhiờn Vit Nam Cựng vi giao din hin i, n gin m thụng minh VNPD hn em n cho ngi s dng nhng tin ớch v giỏ tr d liu cao phc v cho cỏc mc ớch nghiờn cu khoa hc tng lai Footer Page 42 of 116 Header Page 43 of 116 KT LUN V KIN NGH KT LUN T nhng kt qu nghiờn cu ó trỡnh by trờn, chỳng tụi rỳt kt lun sau: Bc u xõy dng thnh cụng CSDL cỏc hp cht cú ngun gc thiờn nhiờn Vit Nam: - Hin ti VNPD qun lý 1376 hp cht vi thụng tin v s ng ký tờn hp cht VNPD_ID t n 1376; tờn thụng thng; tờn IUPAC; cụng thc; nh dng biu din dũng (SMILES, InChi, InChiKey); phõn loi nhúm cu trỳc; thụng tin v cỏc thụng s lý húa ca hp cht (khi lng phõn t, XlogP, s liờn kt cho Hydro, s liờn kt nhn Hydro, s vi phm quy tc S ca Lipinski, s liờn kt xoay ng v, din tớch b mt ht mang in v MACCS); thụng tin v ngun dc liu (tờn ngun dc liu, tờn khoa hc, h thc vt, a im thu mu, thi gian thu mu, b phn dựng, tỏc dng dõn gian, tỏc dng dc lý c chng minh); ti liu tham kho - ó tin hnh phõn tớch c im cu trỳc sp xp cỏc hp cht vo nhng nhúm phõn loi riờng (nhúm chnh, nhúm ph) Cỏc hp cht c xp vo 11 phõn loi nhúm chớnh; s a dng cỏc cu trỳc húa hc cho thy tim nng v thuc ca cỏc hp cht - Nhng tớnh toỏn thc hin trờn cỏc hp cht cú VNPD cho thy hn 85% cú tớnh cht húa lý y hn, da trờn Quy tc s ca Lipinski, õy l nhng ng c viờn tim nng cho vic phỏt trin thuc t cỏc hp cht cú ngun gc t nhiờn ó thit k v xõy dng c mt CSDL cỏc hp cht cú ngun gc t nhiờn Vit Nam trờn giao din web mang tờn VNPD (Vietnam Natural Products Database) Vi cỏc d liu hin VNPD ang qun lý, cú th s dng sng lc o cỏc hp cht trờn cỏc ớch khỏc nhm phỏt hin cỏc hp cht mi cú tim nng phỏt trin thnh thuc Footer Page 43 of 116 Header Page 44 of 116 KIN NGH tip tc phỏt trin v hon thin CSDL, chỳng tụi xin a cỏc xut sau: Tin hnh tớnh toỏn cu trỳc 3D ca tt c cỏc hp cht phc v cho cỏc nghiờn cu sng lc insilico iu ny m bo rng vic ng dng CSDL s c ti a húa v cú th s dng cỏc thụng tin phc hp sng lc i vi nhiu mc tiờu v thuc Vic truy lc d liu c, liờn quan n cỏc ti liu tham kho bờn ngoi s c tin hnh xỏc minh cỏc thụng tin trớch ra, cng nh b xung thờm DOI (Digital Object Identifier) s chng minh vt th, vo cựng cỏc ti liu tham kho h thng húa VNPD lờn ngang tm vi cỏc CSDL quc t Mi hp cht CSDL c liờn kt vi ớt nht mt ti liu tham kho bờn ngoi S dng CSDL ó xõy dng c, tin hnh sng lc o trờn cỏc ớch sinh hc khỏc nhm phỏt hin cỏc hp cht mi cú hot tớnh sinh hc Footer Page 44 of 116 Header Page 45 of 116 Ti liu tham kho [1] 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HỌC QUỐC GIA HÀ NỘI KHOA Y DƯỢC NGUYỄN THỊ THU HÀ BƯỚC ĐẦU XÂY DỰNG CƠ SỞ DỮ LIỆU CÁC HỢP CHẤT THIÊN NHIÊN VIỆT NAM PHỤC VỤ CHO VIỆC SÀNG LỌC ẢO KHÓA LUẬN TỐT NGHIỆP DƯỢC SĨ ĐẠI HỌC Khóa: QH.2012.Y... tin cho nhiều người sử dụng nhiều ứng dụng khác CSDL hợp chất có nguồn gốc tự nhiên Việt Nam xây dựng với mục đích tập hợp quản lý hợp chất phân lập từ thảo dược Việt Nam nhằm phục vụ cho việc sàng