Discovery of Human HMG-Coa Reductase Inhibitors using...

Abstract—3-hydroxy-3-methylglutaryl coenzyme A reductase

(HMGR) catalyzes the conversion of HMG-CoA to mevalonate using NADPH and the enzyme is involved in rate-controlling step of mevalonate. Inhibition of HMGR is considered as effective way to lower cholesterol levels so it is drug target to treat hypercholesterolemia, major risk factor of cardiovascular disease. To discover novel HMGR inhibitor, we performed structure-based pharmacophore modeling combined with molecular dynamics (MD) simulation. Four HMGR inhibitors were used for MD simulation and representative structure of each simulation were selected by clustering analysis. Four structure-based pharmacophore models were generated using the representative structure. The generated models were validated used in virtual screening to find novel scaffolds for inhibiting HMGR. The screened compounds were filtered by applying drug-like properties and used in molecular docking. Finally, four hit compounds were obtained and these complexes were refined using energy minimization. These compounds might be potential leads to design novel HMGR inhibitor.

Keywords—Anti-hypercholesterolemia drug, HMGR inhibitor, Molecular dynamics simulation, Structure-based pharmacophore modeling.

I. INTRODUCTION HE 3 hydroxy-3-methylglutary coenzyme A reductase (HMGR) catalyzes the conversion of HMG-CoA to

mevalonate using two molecules of NADPH as cofactor and the enzyme is involved in rate-controlling step of mevalonate pathway which is related with biosynthesis of cholesterol and other isoprenoids [1]-[2]. Structure of HMGR was represented in Fig. 1. Structurally, human HMGR monomer consists of three domains: (1) The small, helical amino-terminal N-domain

Minky Son is with the Division of Applied Life Science (BK21 program), Gyeongsang National University (GNU), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Republic of Korea (phone: +82-55-772-1360; fax: +82-55-772-1359; e-mail: [email protected]).

Chanin Park is with the Division of Applied Life Science (BK21 program), Gyeongsang National University (GNU), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Republic of Korea (e-mail: [email protected]).

Ayoung Baek is with the Division of Applied Life Science (BK21 program), Gyeongsang National University (GNU), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Republic of Korea (e-mail: [email protected]).

Shalini John is with the Division of Applied Life Science, Gyeongsang National University (GNU), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Republic of Korea (e-mail: [email protected]).

Keun Woo Lee is with the Division of Applied Life Science (BK21 program), Gyeongsang National University (GNU), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Republic of Korea (phone: +82-55-772-1360; fax: +82-55-772-1359; e-mail: [email protected]).

(2) The large, central L-domian that contains the dimerization motif ENVIG (3) The small, S-domain which is inserted into the L-domain and contains a NAD(P) binding motif DAMGMN [1]. Inhibition of HMGR is considered as effective way to lower cholesterol levels so it is drug target to treat hypercholesterolemia, major risk factor of cardiovascular disease. So far, several statins are well known as HMGR inhibitors and some of these drugs are used in treating patients with cardiovascular disease. Statins have HMG-like moiety and bind to the active site of HMGR instead of substrate [3]. However, several reports reveal that statins cause diverse side effects such as eczema, sensory disturbances, depression, and muscle weakness [4]-[7]. Therefore, there is a need for developing HMGR inhibitor design to have potent activity and fewer side effects. In this study, to discover novel HMGR inhibitor, we performed structure-based pharmacophore modeling combined with molecular dynamics simulation approach. Four inhibitors including two statins, named as rosuvastatin and simvastatin, were used for molecular dynamics (MD) simulation study and the representative structure of each simulation were selected by clustering analysis. Four structure-based pharmacophore models were generated using the representative structure of structures of each complex. The generated pharmacophore models were validated using data set and used in virtual screening process to find novel scaffolds for inhibiting HMGR protein. The screened compounds were then filtered by applying drug-like properties and used in molecular docking calculation. As a result, four hit compounds were obtained and these complexes were refined using energy minimization. These compounds with chemical modifications might be virtual leads for HMGR inhibitor design.

Minky Son, Chanin Park, Ayoung Baek, Shalini John, and Keun Woo Lee

Discovery of Human HMG-Coa Reductase Inhibitors using Structure-Based Pharmacophore Modeling Combined with Molecular Dynamics Simulation

Methodologies

T

World Academy of Science, Engineering and TechnologyInternational Journal of Medical, Health, Pharmaceutical and Biomedical Engineering Vol:7 No:1, 2013

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http://waset.org/publication/Discovery-of-Human-HMG-Coa-Reductase-Inhibitors-Using-Structure-Based-Pharmacophore-Modeling-Combined-with-Molecular-Dynamics-Simulation-Methodologies/7185

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Fig. 1 Dimeriepresented maggands in two ide

Fig. 2 Chemica

A. Preparatio3D structures

vailable in Prelected compleode 1DQA). U

with four diffeased on inhibised dimeric foemoved.

B. MolecularIncluding ap

mulation studGROMACS 410]-[11]. Whilor inhibitors anirst of all, the protein were fixructure was porotein surface 13]-[14]. Somounter-ions to

c structure of hgenta and cyan rentical active st

yellow (Co

l structure of foIC

II. M

on of Systems s of human HMrotein Data Bex structure w

Using this struferent HMGRitory activity aorm of the pro

r Dynamics Sipo form, five dy. All simu.5.3 packagele preparing, tond cofactors wprotonation stxed to pH7 andositioned in cuand then solv

me water moneutralize the

human HMGR. ribbon model, rties were displaoA) stick mode

our HMGR inhbC50 value

METHODS

MGR includinank. Among

with HMG, CoAucture, we builR inhibitors wand their scaffotein and all w

imulation systems werulations were with CHARopology and f

were generatedtates of all the d hydrogen atoubic water bo

vated using TIolecules weree system. After

Each monomerrespectively andayed as red (NAels

bitors along wit

ng ligand bounthese structuA, and NADPlt complex str

which were sfolds [3], [8]-

water molecule

re prepared fe carried outRMM27 forcforce field parad by SwissPara

ionizable resioms were addx with 10 Å frP3P water mo

e replaced wr that, the syst

r was d bound

ADP) and

th their

nd were res, we

P+ (PDB ructures selected [9]. We es were

for MD t using

ce field ameters am [12]. idues in

ded. The from the olecules

with Na tem was

subdepeeqns the[15intva(PMan[20calwaunstrtheroonusquim

weDigefeaproa sDeprobonecoprototscophphFinrep

Sc

wiredThallLigvaanscavirphAS

bjected to enescent algoritrformed for

quilibrate the sproduction ru

e geometry o5]-[16] and teraction energ

an der Waals ME) algorithm

nd temperature0] barostat ulculation of faas applied. Tonder periodic bructure of eache trajectories fot mean squa

umber of intruare fluctuati

mplemented in

C. Structure-BStructure-bas

ere generatediscovery Studneration protoatures on the otein and subssphere for theefine and Edioperties such

ond donor (HBgative ionizansidered as poperly adjust tal ten hypothore. Top-sco

harmacophore harmacophoricnally four phapresentative st

D. Validationreening Final pharma

ith data set coductase inhibihese inhibitorsl inhibitors wgand Pharma

alidation procend the rest comaffold which srtual screenin

harmacophore SINEX, Chem

ergy minimizathm. Next,100 ps unde

system and equns. During thf water moleSETTLE alg

gies like long-were calcula

m [18]-[19] ae were maintausing Berendsfast Fourier trao evade edgeboundary conh system, clusfrom 4 ns to 10are deviationsa and inter hion (RMSF) wGROMACS.

Based Pharmased pharmacopd using the

dio (DS) v3.1.ocol available

basis of intestrate. In the pe calculation it Binding Sias hydrogen

BD), hydrophable (NI) anpharmacophorto handle the

heses were oboring hypot

model andc features nearmacophore tructures.

n of Pharm

acophore modonsisting of 1itors, and 89 s have inhibit

were used in acophore Mapess and 12 HMmpounds of dsatisfy pharmang process wa

models. In thmbridge, Mayb

ation of 10000 position reer NPT cond

quilibrated syshe productioncules were regorithm [17],-range electrosated using pa

and cut-off of ained using asen thermostaansform, grid e effects, the nditions. To oster analysis w0 ns. All others (RMSD), phydrogen bonwere done thr

acophore Modphore modelseir representa. Receptor-lige in DS produeraction betwpharmacophorwas defined aites tool in Dbond accepto

hobic (HYP), nd positive ioric features anflexibility of

btained and rathesis was d it was cecessary to models were

macophore M

del of each sy12 HMGR inh

glutathione rtory activity wenergy minim

pping protocoMGR inhibitorsdata set as inaacophoric featas performed he stage, four bridge, and N

0 steps using stestrained MDditions at 30stem was used

n runs, all bonestrained by L, respectivelystatic interactiarticle mesh

f 14 Å. The pra Parrinello-Rat [21]. In cspacing withsimulation w

obtain represewas performedr analyses contotential energ

nds, and rootrough analysi

del Generations of four comative structu

gand pharmacuces pharmacoween the residre model geneat the active DS. Basic chor (HBA), hyring aromaticonizable (PI)nd parameterprotein. As a

anked by selechosen as

comprised ofinhibitory acobtained from

Model and

ystem was vahibitors, 361 reductase inhiwith IC50 valumization usin

ol were used s were used asctive. To findtures of each musing the vadata bases nam

NCI were emp

teepest D was 00K to d in 10

nds and LINCS y. The ion and Ewald

ressure Rahman case of h 1.2 Å was run entative d using taining, gy, the t mean is tools

n mplexes ure by ophore

ophoric dues of eration, site by

hemical drogen

c (RA), ) were s were result,

ectivity final

f vital ctivity. m four

Virtual

alidated aldose

ibitors. ues and ng DS.

in the s active d novel models, alidated med as ployed.


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Thth(A[2codo

drmOCrthinsitGeapowwprmthbiinancoalcoGw

bachinINcostcadiapanco

cofoflemchshno

he screened cheir drug-likenAbsorption, D23] properties ompounds paocking calcula

E. MolecularThe compo

rug-likeness molecular doc

ptimization frystallographi

he docking fnhibitors), the te were defin

GA runs was iarly terminatiooses were wit

was quitted andwere then rankredicted bindin

molecular interhe selected cominding free enteraction of lind estimatesonformations olgorithm (LGAompounds, e

GROMACS anwere done with

A. ConstructiTotal four H

ased on highlhemical structnhibitors have NH1 and INompounds. INatins, called ase of INH3 wiffered in conpproved statinnd triglyceridomplexes were

B. Molecular10 ns MD

omplex (TABorm to investigexibility whe

models. Prior hecked using hown in Fig. 3o abnormal co

ompounds froness. Lipinskiistribution, Mwere calcula

ssing all criteation.

r Docking andounds selecte

properties ccking study for Ligand Dic Data Centrfor hit and residues withed as bindingincreased up on option wasthin the RMSd moved on thked according ng conformatiractions in thempounds fromenergy using igands with bis the bindinof flexible ligA). To refine

energy minimnd all structurh these structur

III.

ion of ProteinHMGR inhibitly active and ture of four inHMG-like mo

NH2 were pyNH3 and INH

rosuvastatin was structurallntaining sulfu

n drugs and wides in the e used in MD

r Dynamics Sisimulation s

BLE I) includigate structuralen developing

to analysis, RMSD and

3, all simulationformational

om this stage i’s rule of fiv

Metabolism, Exated via DS. Ieria were sel

d Energy Minied from virtcalculation w

using GOLDocking), frre, Cambridge

reference chin 15 Å fromg site for calcu

to 50 for accs used for effiD value of 1

he next ligand.to GOLD fitn

ion of hit come active site o

m molecular doAutoDock

omacromolecng free enands based one complex strmization wasral analyses ofres.

RESULTS

n-Inhibitor Cotors were chotheir scaffold

hibitors with oiety and poteyrrole-based

H4 were knowand simvastaly similar with

fur atom. INHidely used for

blood. Fousimulation st

imulation of Fstudy was peing apo form l changes and tg structure-ba

overall stabipotential eneons were stabchanges.

were sorted tove [22] and Axcretion and TIn the last stalected for mo

imization tual screeninwere subjecLD 5.0.1 (Grom the Came, U.K [24]-[

compounds (m the center oulation. The vcuracy. Additiiciency so if a.5 Å, the calc. The resultanness score. Fr

mpounds, we anof HMGR. In ocking, we cal4.2. It predi

cular targets [2nergy upon n Lamarckian ructures of fis performed f final hit com

mplex osen from liteds. Fig. 2 reptheir IC50 valu

ent inhibitory and pyrazole

wn for a mematin, respectivh other statinsH4 was one lowering cho

ur HMGR-intudy.

Five Complexerformed usinand inhibitor

to consider strased pharmacility of systergy calculatio

ble during 10

o check ADMET Toxicity) age, the olecular

ng and ted to Genetic mbridge [25]. In HMGR f active

value of ionally,

any five culation nt poses rom the nalyzed case of

lculated icts the 26]-[27]

bound genetic

final hit using

mpound

eratures presents ues. All activity. e-based

mber of vely. In s, but it of the

olesterol nhibitor

ng five r bound ructural cophore em was ons. As ns with

Str

strIn wevaanreswaapstr1.0an

Fi

inhhycashyN7obwiintHME5

12345

C. Comparisoructure from CTo compare

ructure from 6the cluster an

ere statisticallyalue and the vand 0.134 nm inspectively. Fras selected as o form was s

ructural deviat05 Å (INH1-A

nd 1.35 Å (INH

ig. 3 RMSD anenergy d

D. Binding MBinding modhibitors show

ydrogen bond se of HMGR

ydrogen bonds755, and NAbserved in INHith fluorophenteraction witMGR-INH2 co559, S565, K7

F

No Apo INH1INH2INH3INH4

on of Five Cluster Analys each syste

6000 structurenalysis, confory classified as

alue is 0.135 nmn Apo, INH1, rom the clustrepresentativ

superimposed tions were noApo), 1.2 Å (IH4-Apo), resp

nd potential enerduring 10 ns MD

Mode of Four Hde of four inhwed reasonabnetwork with

R in complex s with R590, ADPH. Also,H1 binding; Rnyl group oth phenyl gomplex, the re735, N755, an

TAFIVE COMPLEXES

System

Complex Ussis m, we obta

es after 4 ns usrmational fams clusters accom, 0.132 nm, INH2, INH3, er analysis, te structure of with each in

ot much with INH2-Apo), 1

pectively.

rgy plots. (a) CD simulations o

HMGR Inhibithibitors was shble binding active site reswith INH1, tS684, K691,

hydrophobicR590 formed f INH1 and group of INesidues such and NADPH w

ABLE I S USED IN THIS ST

HMGR_NADHMGR_NADHMGR_NADHMGR_NADHMGR_NAD

sing Represe

ained represesing cluster an

milies of each ording to the 0.126 nm, 0.1and INH4 co

the middle strf each system.nhibitor bound

the RMSD va1.09 Å (INH3

α RMSD (b) poof all systems

tors hown in Fig. mode and fsidues of HMthe inhibitor fS565, A751,

c interactionscation-π interS865 forme

NH1. In caas R590, D690were participa

TUDY

details DPH DPH_INH1 DPH_INH2 DPH_INH3 DPH_INH4

entative

entative nalysis. system cut-off 27 nm, mplex, ructure When

d form, alue of

3-Apo),

otential

4. All formed

MGR. In formed K735,

s were raction ed π-σ ase of 0, K691, ated in


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hybeHreanHRNwstrop

FI

wrebephsyrepr12

quFrfedrAwC

ydrogen bondetween INH2

H866 and H869esidues R590, nd NADPH ha

HMGR-INH4 c590, S684, D

NADPH. Unlikwas not found i

rong hydrogepposite side of

Fig. 4 Binding mINH1, (b) INH2blue, green, andrawn as yello

(magenta) an

E. Structure-BTo find nove

we generate sepresentative sest model hharmacophoriystem named espectively. Trocess using d2 HMGR inhib

F. Virtual ScrThe validated

ueries to searrom the screeeatures of eacrug-like prope

ADMET. In thwere retrieved

onsequently,

d interactions and imidazo

9 were detectS684, D690,

ave involved complex, INHD690, E559, ke three other sin INH4 bindien bonding wf S565.

mode of four H2, (c) INH3, andnd orange stick ow stick model.nd hydrophobic

Based Pharmel scaffolds fostructure-basestructure of eahaving high c features as fas Pharm 1,

These modeldata set. All phbitors in data

reening and Dd four pharmarch virtual leening, compouh model were

erties calculatihis process, 1by Pharm 1, we identified

with INH2. le rings of ared. In HMGRK691, S565,in hydrogen b

H4 has formed K735, H752

systems, hydroing and this w

with S865 whi

HMGR inhibitord (d) INH4 wermodel and activ Dash lines ind

c interaction (ye

macophore Moor Anti-hypercd pharmacopch system. In

selectivity final pharmaco

Pharm 2, Phs were subj

harmacophoreset.

Drug-Like Proacophore modads for HMGunds mappede selected andion like Lipin160, 419, 110Pharm 2, Pha

d 105 compou

The π-π interromatic residuR-INH3 comp K735, N755bonds with INhydrogen bon

2, N755, S86ogen bond wit

was mainly duich is located

rs at the active sre shown as as pve site residues

dicate hydrogen ellow), respectiv

dels cholesterolemiphore modelseach case, wescore and

ophore model harm3, and Phected to vals successfully

operties dels were usedGR inhibitor d on pharmacod then filteredski’s rule of f, and 64 comarm 3, and Phunds that com

ractions ues like lex, the , H869,

NH3. In nds with 65, and th S565

ue to the on the

site. (a) purple, s were

bond vely

ia drug, s using chosen diverse of each

harm 4, lidation

y picked

d as 3D design. ophoric d using five and

mpounds harm 4. mmonly

premostu

FPh

an

doGOINscoanTaco

obcoPhhigHyfouatocarintatohyscousinubofeaH7attha-8.Hi

esent in the scodels and thesudies.

Fig. 5 Structure-harm 1, (b) Pharnd NI features w

G. Selecting FWith four H

ocked into actiOLD fitness sc

NH2, INH3, anore and mole

nd binding freeaken together,mplexes were

H. Binding MFour structur

btained after enmpounds wer

harm 1 and Phaghest value oydrogen bondund at almost om of H866rboxylic acidteracted with om connectinydrogen bond wore of 78.01 aing Pharm 2 a

umerous interonds between atures and re752, N755, Stained from vias GOLD fitne.01. Several acit 3. The resid

creening resulse compounds

-based pharmacrm2, (c) Pharm3were represente

color, r

Final Hits usiHMGR inhibitive site of HMcore of 50.74,nd INH4, respcular interact

e energy was c, four hit come refined by en

Mode of Final Hres in complexnergy minimizre shown in Fiarm 3 and GOof 87.02 and d interactions

oxygen atom was also h

d moiety in S565 from t

ng the two phwith R568. Seand binding frand Pharm 3.ractions with butyramide m

esidues like SS852, and H8irtual screeniness score of 7ctive site residdues R590, S

lts by at least s were used fo

cophore models3, and (d) Pharmed in green, marespectively

ng Moleculartors, total 10

MGR. Four HM 53.81, 52.17,pectively. Bations, we selecalculated usinmpounds werenergy minimiz

Hit Compounx with final hzation. Bindinig. 6. First, Hi

OLD fitness scbinding free

s with active ms existent in Hhydrogen bonHit 1 and n

the other monhenyl rings ofecond, Hit 2 sfree energy of This compouactive site

moieties of HS684, K692, 866 were obsng through Ph75.76 and bindues formed h684, and K69

two pharmacor molecular d

s of each complm 4. HBA, HBDagenta, cyan, an

r Docking 09 compoundsMGR inhibitor, and 53.05 for

ased on these ected 32 compng these compe obtained andzation.

ds hit compoundng modes of fit 1 was identifore for Hit 1 w

e energy was site residues

Hit 1. The hynded to oxygneighboring onomer. The of Hit 1 was fcored GOLD

f -6.94 was retund also has fresidues. Hy

Hit 8 matchingS565, R568, erved. Third,

harm 1 and Phnding free enehydrogen bond92 formed hy

ophore docking

lex. (a) D, HYP, nd blue

s were rs have r INH1, fitness

pounds pounds. d these

ds were final hit fied by was the

-7.77. s were drogen gen of oxygen oxygen formed fitness trieved formed drogen g HBA

K735, Hit 3 harm 3 ergy of ds with drogen


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boHnesuHengrS6hyhyatinhyThfaThcose

h

anobpo

PrPrPrFoEdKND

onding with cHit 3 has hydroeighboring NHulfonyl moiety

H866. The lastnergy for Hit 4roups of Hit 4 684, and K6ydrogen bondydrogen bondtom close to pnteraction withydrogen bondhe binding m

avorable molehe novelty ofonfirmed usingearch [29].

Fig. 6 BindingHit 2, (c) Hit

magenta, cyahydrophobic int

Inhibition ofnti-hypercholebtained from ootent inhibitor

This researcrogram (2012rogram (2009-rogram (201oundation of ducation, Scie

Korea. And Next-Generatio

evelopment A

arboxylic acidogen bond inteH group wasy made hydrot hit, the GOL4 were 72.18 showed hydr

692, especial. The piperidi

ds with hydropiperidine grouh H866. The bd interactions wmode analysis ecular interactf final hits fg SciFinder sc

g conformation3, and (d) Hit 4an, and brown steractions were

IV. Cf HMGR enzesterolemia drour study mighr of HMGR.

ACKNO

ch was suppoR1A1A4A010-0081539), an0-0029084)

f Korea (NRence and Tecthis work

on BioGreen 2Administration

d moieties of Heractions withs hydrogen boogen bonds wLD fitness scoand -7.87, resogen bond intlly K692 haine group of Hogen atoms oup was also shbutyramide mowith S565 andindicates tha

tions at the acfor the inhibitcholar [28] an

n of final hit com4 were representstick models. Hshown as gray

CONCLUSION zyme is consrug developmeht be potential

OWLEDGMENT orted by Basi013657), Pion

nd Managementhrough the

RF) funded bchnology (ME

was also 21 Program (Pn (RDA) of Re

Hit 3 thiazoleh K691 and N7onded to E55

with C561, S86ore and bindispectively. Twteractions withas formed trHit 4 formed bof N755 and hown hydrogeoieties of Hit d S865, respeat all final hictive site of Htion of HMGd PubChem st

mpounds. (a) Hted in yellow-g

Hydrogen bond and orange das

sidered as a ent. Four coml leads for dev

ic Science Rneer Researchnt of Climate C

National Rby the MiniEST) of Repusupported bJ008038) fromepublic of Ko

e ring in 755 and 59. The 65, and ing free

wo ether h R590, ripartite bipartite oxygen

en bond 4 made ctively. ts have

HMGR. GR was tructure

Hit 1, (b) green, and sh lines

way of mpounds

eloping

Research h Center Change

Research stry of ublic of by the m Rural rea.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10

[11

[12

[13

[14

[15

[16

[17

[18

[19

[20

[21

[22

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