Hiia Thi Toan vd Dig Tap chi KHOA HOC & C 6 N G N G H E 169(09)'29-32
CONG NGHE SANG LQC AG, DOCKING PROTEIN VA MOT SO UNG DUNG TIEU BIEU
Htta Thj Toan^', Nguyen Thj Thuy', Trttong Due Cuong' 'Trudng Dgi hgc Nong Lam - DH Thdi Nguyen,
^Tivcmg Cao dang Kmh te Ki thugt—DH Thai Nguyen
T O M T A T
Trong vdng 60 nam qua, khoa hoc cdng ngh€ d3 va dang phat tnen mot each chong mat. Hang loat cac san pham cong nghp cao duoc ra ddi nhu dien thoai cam iing, may tinh sieu nang, dong ho dien thoai Tuy nhien, trong l&ih vuc cham soc sire khoe, ma cu the 1^ duoc hpc, so luo^ig thuoc mdi ra ddi ngay cang giam di [8] Con s6 nay that dang lo ngai khi tren the gidi co hang tr5m loai bpnh tat, va nguy hiem hon khi nhiing loai benh khdng co thuoc tq ngay cang gia tang NhSm giai quyet tinh trang cap bach tren, cac nha khoa hoc da dua ra mot so chien luge trong qua trinh nghien ciru, trong do sir dyng cdng n g h | sikng loc ao thong qua su trcr giiip ciia may tinh la hudng nghien cim mdi duoc cac nha khoa hpc ap dung trong phat tnen thuoc pho bien hien nay. Trong bai bao nay, diiing tdi gidi thieu ve cdng nghe nay va mdt s6 ling dung ciia no trong nghanh cdng nghiep che bien thuoc.
Tir khoa: Sdng Igc do, docking phdn tu, in silico. protein, enzyme
DATVANDE
Hien nay, vdi nhiing thanh ttm v u p t bgc trong khoa hpc may tinh va nhiing hieu biet sau hem trong ITnh vuc sinh hoc phan tii, nhieu linh vyc nghien ciiu d u a tren sir trg giup cua may tinh da d u g c hinh thanh v a cho ket qua iing dung cao, Cac p h u o n g phap trg giup bdi may tinh d u p c ling dung vao nhieu khau ciia qua trinh nghien ciiu va phat t n e n thuoc, tir khau tim kiem cac h g p chat hda hoc cd tac dyng sinh hpc, den toi u u hda cau tnic cac hgp chat nay nhSm tang hogt tinh sinh hpc, giam dpc tinh, tang cac tinh chat d u g c dpng hpc ciia thuoc, den cac khau nghien ciiu tien lam sang va lam sang. Chiing d u o c gpi chung la cac phuong phap sang lpc ao - in silico.
So vdi cac p h u o n g phap t h y c nghiem truyen thong, sang Ipc ao cd u u the giiip thiet ke nhirng phan t u thuoc m d i vdi nhung uu the vuot trpi, giai thich ban chat phan tii ciia cac tuong tac thuoc, dieu m a khdng mpt thi nghipm nao cd k h a nang Iam dugc Ngoai ra chiing cho phep dy doan hogt tinh sinh hoc su dyng cac md hinh toan h p c , nghien ciiu d u doan CO che tac dyng, c o che gay dpc cua cac
* Tel: 0984 041052, Email:
hop chat. Cac phuong phap nay giiip tiet kiem dang k^ ca thoi gian va tien bac trong viec phat trien mpt thuoc mdi.
K E T QUA N G H I E N C U V
Gidi thiSu c h u n g ve m o h i n h s a n g l^c ao Trong cac sang Ipc hoat chat hien dgi, phuong phap sang loc ao in silico (virtual screening) ddng mpt vai trd het siic quan trong, Phuong phap tren sii dung cac tien bp trong tin hpc de md ta va dy doan cac cau tnic mdi duoc cho la cd hogt tinh mgnh. Uu diem ciia phuong phap la giam thieu chi phi va thdi gian trong qua trinh phat hipn va phat trien thuoc, Quy trinh nghien ciiu va san xuat thuoc mdi cd the d u p c torn t i t qua 4 b u d c c a ban [8] • - Tim kiem hogt chat tiem nang' Hang loat cac chat trong ty nhien va nhan tao duoc tien hanh thii nghiem trong phdng nghien cuu tren cac mo hinh benh tat khac nhau, bao gom ca thiet ke thuoc tren may tinh,
- Thir nghiem tien lam sang: Cac hogt chat tiem nang se dugc tien hanh thii nghiem tren dpng vat vdi m u c dich chinh la xac dinh kha nang dieu tri cung n h u dp an toan ciia hoat chat tren co the song, dgc biet la c a the cd hp thong giong con ngudi
Hiia Thi Toan vd Dig Tap chi KHOA HOC & CONG NGHE 169(09), 29-32 - Thii nghiem lam sang; Cac hogt chat cd tac
dung tot tren ddng vat se dugc tien hanh thii nghiem tren ngudi tinh nguyen.
- Dang ky thuoc va dua ra thi trudng Nhu vgy, md hinh sang Ipc ao dugc ap dyng trong budc dau ciia quy trinh nghien ciiu va phat trien thuoc mdi dd la nham lim ra cac hogt chat cd tac dung tot nhat, lieu lugng thap nhat va an toan nhat. Vdi cac he thong may tinh noi mang hien dgi thi hang tripu cau tnic cd the duoc sang Ipc ao chi trong thdi gian vai tuan. WISDOM (Worid-wide in Silico Docking On Malana) la mpt du an thanh cong sii dung Grid trong vi^c sang Ipc va phat trien thuoc chong sot ret tren he thong cac may duoc noi mang tren toan the gidi Ban chat ciia md hinh nay dya tren ca che sau Dich den ciia cac phan tu thuoc thudng ia nhiing phan tii protein hoac enzyme lien quan den mpt trgng thai bpnh ly neng biet va thuoc h§ thong truyen tin hieu te bao hoac trao ddi chat dgc trung. Do vgy, cac loai thudc dugc thiet ke de ire che, hoi phyc hogc bien doi cau tnic hogc phucmg thiic hoat ddng ciia protein, enzyme lien quan den benh ly, Sau khi tgo dupc mot ngan hang cau tnic ciia cac phan tii thuoc, nhiing phan tii cd hogt tinh sinh hpc mong muon cd the duac sang Ipc theo hai each, phuang phap thi nghipm hoac bang each md phdng true tiep vdi phan tu protein dich roi danh gia cac chi tieu ly hoa, dpng hoc [7].
Cac sang ipc in silico sir dung cac tuang tac giiia Docking - Ligand de tim ra cac cau tnic ma lien ket vdi thy the tot nhat - d day la cd miic nang lupng " AG thap nhat. Cau tnic cac Key Protein 3D doi vdi moi bpnh dugc cung cap bdi cac nha sinh hpc, cac ligand dupc phat trien dya theo cau tnic ciia cac hgp chat
hoa hpc, dgc biet la cac bp khung cacbon dH dugc biet ro rang va cd nguon cung cap.
KT thuat Protein docking
Protein docking la ki thugt mo hinh hoa nham du doan vi tri va cau hinh thugn Ipi ma phan tli CO chat cd the gan ket tren phan tir protein, Phan tli ca chat dupc cho dich chuyen trong khong gian bao quanh phan tii protein de tim vi tri cd nang lupng gan ket am nhat sii dyng cac ham danh gia va phuang phap tim kiem cue tri toan cue khac nhau [6] Docking co vai trd quan trpng trong vipe dy doan ai luc va hogt tinh ciia cac dugc chat doi vdi protein, tir do du doan kha nang hoat hda hoac lie che mdt protein chiic nang Ben canh do docking Cling giup dy doan tam hogt dpng va vi tri, cau hinh thugn Igi ciia ca chat tham gia phan ling khi xem xet ca che xuc tac ciia enzyme (ciing la mot logi protein chiic nang).
Docking trd thanh bai toan toi uu, tim vj tri va cau hinh phii hgp nhat cua mpt ca chat gan ket Ien protein, Ve mgt nhipt dpng Iyc hpc, muc tieu cua docking la tim ra cau hinh ma nang lugng tu do ciia toan hp la thap nhat. Dp tim cau hinh phu hop nhat can phai lien hp khong gian cau hinh vdi cac gia tri so danh gia dugc kha nang gan ket ciia ca chat len protein roi mdi ap dyng dugc cac thugt toan tim kiem.
AutoDock 4.2 la phien ban mdi nhat trong chuoi phan mem AutoDock, san pham ciia The Scripps Research Institute. Day la phan mem ma nguon md dupc sii dyng vdi myc dich khao sat docking doi vdi cac hgp chat can phan tich. AutoDock 4.2 dugc diing kem vdi AutoDockTools 1.5.4 de ho trg giao dipn do hpa. Cac budc tien hanh
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Qua trinh tuang tdc giua Docking - Ligand
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Hira Thi To^n vd Dig Tap chi KHOA HQC & C 6 N G N G H $ 169(09): 29 - 32 - Chuan bi protein va ligand.
- Tinh toan ban do ai Iyc sii dyng cong cu autogrid4 (3D).
- Xac dinh cac tham so docking va tien hanh tinh toan md phdng docking.
- Phan tich ket qua.
- Quy trlnh san xuat Mot so irng dung tieu bi€u
Nhung nam gan day da cd nhieu cong trinh khoa hpc cong bo nhung nghien ciru lien quan tdi viec iing dung sang Ipc ao de tim ra cac chat CO hoat tinh chua benh
- Tap the nghien ciru ciia GS.TS Phgm Quoc Long, PGS.TS Le Mai Huong (Vipn Hda hpc cac hpp chdt thien nhien), TS. Vii Trpng Hieu (Vien Cong nghe thong tin), TS. Bui The Quang (Vien Tin hoc Phap Ngu) da va dang tgp trung vao hudng nghien cuu iing dyng cdng nghe sang Igc ao trong vipe tim ra cac hop chat thien nhien cd nguon goc tir thuc vgt va sinh vat bien Vipt Nam Nhdm da thuc hien thanh cdng 01 de tai hgp tac quoc te giiia Vien Han Lam Khoa hpc va Cong nghe Viet Nam vdi phong thi nghipm Vat Ii hgt nhan - Cpng hda Phap (LPC-CNRS) trong nghien ciiu ling dyng cong nghp sang Ioc ao de phat hien cac chat c6 hogt tinh chong sot ret va nhieu de tai khac lien quan den benh ta, bpnh Alzheim6r[5]
- Nhdm nghien ciiu ciia TS. Le Thi Thu Hudng (DH Quoc Gia Ha Npi) da cd mpt so cong trinh nghien ciiu iing dung sang loc ao de tim va thiet ke cac hop chat cd hoat tinh sinh hpc, lua chpn nhimg chat cd tiem nang phat trien thanh thuoc, ngoai ra nhdm cdn cd mpt hudng tiep can khac la tim kiem cac hogt
•chat mdi cd hogt tinh sinh hoc tir nhtrng thuoc dang dugc su dyng nham giam chi phi thu nghiem lam sang va nhanh chdng dua san pham ra thi trudng[2].
- Da cd nhieu cong trinh khoa hpc cdng bo nhiing nghien ciiu lien quan tdi vipe sang lpc hogt tinh ciia cac hgp chat thien nhien doi vdi nhieu ddng te bao ung thu gan khac nhau, vi dy nhu nhom nghien ciiu ciia Young Sul va cpng su tgi Dai hpc Chungnam (Han Quoc)
da chiing minh dupc hogt tinh chong tang sinh ciia mpt hpp chat thupe nhdm ent- kaurane diterpenoid tren ddng te bao SK- HEPl thdng qua ca che tac dong len AMPK (cam bien trong cac sinh vgt nhan chuan) tir dd kich hogt qua trinh apoptosis ciia te bao[5].
- Mpt nhdm nghien ciiu ciia Zheng Lu tgi Dgi hoc Huazhong (Trung Quoc) ciing da cong bo hogt chat Arctigenin cd kha nang kich hogt apoptosis tren hai ddng te bao ung thu gan HepG2 va SMMC772I va dac bipt khdng co hieu Iyc trpn t^ bao gan thudng [3], Gkn day, nhdm nghien cuu ciia Pham Minh Quan va cong su tai Dgi hpc Paul Sabatier (Phap) da xac dinh dugc mpt nhdm cac hop chat ent- kaurane diterpenoid tir cay Khd Sam Bac bo Vipt Nam cd hogt tinh chong tang sinh tren hai ddng te bao ung thu bieu mo gan HepG2 va Hep3b thdng qua kich hogt qua trinh apoptosis cua te bao [1, 4]
- Doi vdl hudng nghien ciiu sang loc ao sii dyng cong nghp tinh toan hieu nang cao, da cd mgt so cong bo gan day trong viec tim cac hgp chat cd tiem nang lic che lien ket giiia protein p53 va protein Mortalin, Nhom nghien ciiu Didik H Utomo va cpng su da thanh cong trong viec xac dinh viing lien ket giiia protein p53 - Mortalin va chi ra dugc rapt so hpp chat cd tiem nang lie che lien-ket tren thong qua qua trinh sang Ioc hp thong ca sd dir lipu ZINC gom 9000 hop chat (http://zinc docking,org) (Hinh 2)
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Hinh 2: Mo phong cdc hgp ehdt cd tiem ndng ire chi vung lien kit giira protein Mortalin — p53 Nhin chung, cac nghien ciru ve iing dyng cdng nghe sang lpc k) de tim va thiet ke cac
Hija Thi Toan va Dig Tap chi KHOA HOC & CONG NGHE 169(09) 2 9 -
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hogt chat tipm nang phat t n e n thudc van cdn la chii de mdi v a chua cd nhieu cong trinh cong bo d Viet N a m .
KET L U A N
Bai bao dS d u a ra dugc nhiing khai niem tong quan nhat ve sang loc ao, docking phan tii va mpt so img dyng lieu bieu trong nude va tren the gidi. Nghien ciiu cong nghe nay la mot trong nhung hudng di cd hipu qua nhat trong nghanh cdng nghiep d u g c pham hien nay
TAI LIEU THAM KHAO 1- Giang P. M , Son P T Lee J J , Otsuka H , (2004), "Four ent - kaurane - type diterpenoids from Croton tonkinensis Gagnep", Chemical and Pharmaceutical Bulletin (Tokyo), Vol 52, pp 8 7 9 - 8 8 2 ,
2 Huong L, T, T,, Gerardo M C M , Yovam M P , Antonio R , Concepcion A , Mahmud T, H, K , (2014), "A rational workflow for sequential virtual screenmg of chemical libraries on searchmg for newtyrosinase inhibitors", Current topics m medicinal chemistry. Vol 14, pp.1473 -1485, 3. PhamM Q., IscacheA L . P h a m Q L , Gairm J, E,, (2015), "Cytotoxic, apoptotic and
sensitization properties of ent - kaurane - type diterpenoids from Croton tonkinensis Gagnep OD Human liver cancer HepG2 and Hep3b cell lines", Fundamental & Clinical Pharmacology, Vol 30, Issue 2, pp.137- 146
4. Son N V , Quan P. M., Hung T N , Hoa N T H , Hung N T., Anh L T-, Giap V D , Hieu V T , Quang B T , Quang N. H , Huong L M , Long P Q , (2011), "Imtial investigapon on in sihco malarial activity of some compounds using molecular docking simulations", Vietnam Journal of Chemistry. Vol 49, No. 2ABC, pp 457 - 461.
5. Sul Y. H , Lee M S , Cha F. Y , Thuong P, T , Khoi N. M , Song I. S., (2013), "An ent - kaurane diterpenoid from Croton tonkinensis induces apoptosis by regulating AMP-activated protein kinase m SK-HEPl human hepatocellular carcinoma cells". Biological and Pharmaceutical Bulletin. Vo\ 36, pp 158-164
6 T6ng Thi Thu Cue, (2015), Gop phdn nghien cuu ca che phdn img Esterase bdng phuong phdp hoa tin, Lu§n an tien sT hoa hpc, DH Quoc Gia Ha NQI, 7 PGS TS Bill Van Le, (2010), Nghien ciki mg dung Tin sinh hgc trong vi?c phdt tnen vacxin vd thudc. KC 04 18/06-10, BO Khoa hpc va C5ng ngh$
8 Pham Duy Toan, (2016), Nghien cihi thu6c min, hudng di nao cho tuong lai, htlp./'www visonline.org/news/l468466080 S U M M A R Y
S U M M A R Y O F V I S U A L I Z E D S C R E E N I N G T E C H N O L O G Y , D O C K I N G D I V I S I O N AND S O M E T Y P I C A L A P P L I C A T I O N S
Hua Thi Toan'', Nguyen Thi Thuy', Truong Due Cuong^
University of Agriculture and Forestry - TNU.
^College of Economics and Techniques - TNU Over die past 60 j'ears, scientific technology has been growing rapidly A wide range of high-tech products was bom, such as touch phones, super-computers, telephone clocks, etc However, in the field of health care, especially pharmacology, a number of new-bom medicmes decrease [8] This number is womsome when there are hundreds of illnesses in the world, and more dangerously, diseases which have no treatment medicmes are mcreasing In order to address this urgent issue, scientists have put forward a number of strategies in the research process using virtual screening technology through the assist of computers as a new research direction which is applied popularly by scientists in the development of medicines nowadays.
In this article, we present this technology and some applications in the pharmaceutical industry in manufactunng medicines
Keysword: virtual screening, dociang division, In silico, protein, enzyme
Ngdy nhan bdi: 17/4/2017; Ngdy phdn bien: 19/6/2017; Ngdy duyet ddng: 30/9/2017 Tel. 0984 041052. Email- hiiathUoan@gmai! a
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