Abstract
We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50exp). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50exp (pIC50exp = −0.1552·ΔΔGcom + 5.0448, R2 = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles.
Highlights
A training set of 20 pyrrolidine carboxamide family (PCAM) and validation set of 3 PCAMs (Table 1) were selected from a homogeneous series of inhibitors of enoyl-acyl carrier protein reductase (InhA) inhibitors for which experimentally determined inhibitory activities were available from a single laboratory [12]
Structural information from the crystal structure of InhA-PCAM1 complex guided us during preparation of a reliable quantitative structure-activity relationships (QSAR) model of inhibition of the InhA of Mycobacterium tuberculosis (MTb) by pyrrolidine carboxamide inhibitors, which correlated computed Gibbs free energies of complex formation with observed inhibitory potencies
In addition to this QSAR model, we have derived a PH4 pharmacophore model for PCAM inhibitors using a training set of 20 and validation set of 3 PCAMs with known inhibitory activities [12]
Summary
The World Health Organization (WHO) has set as its goal the decrease of incidence of tubercu1.loIsnitsro(TdBuc)taionnd TB-related deaths by more than 90% in the coming 20 years [1]. SeveraSlevreersaelarrecsheagrcrhougrposupwsewreerwe worokrikninggoonn tthhee ddiissccoovvereyryofoIfnhInAhiAnhiinbihtoibrsitnoortsrneqoutirrienqguKiraitnGg KatG activataioctnivwatihoinchwhwicehrewberaesebdaseodnovnavraioriuosusscscaaffffoollddss:: ttrriicclloossaann[9[]9, ]d,ipdhipenhyelneythl eerth[1e0r,1[11],0p,1y1r]r,olpidyirnreolidine carboxcaamrbiodxeam[1i2d]e a[1n2d] aanrdylaarmylaidmeiddeedreivriavtaitviveess[[1133]],, aallll ddisispplalyaiynigngintienrtmeremdiaetdeiaintheibinithoriybiptoorteyncpieost.encies. RecentR3lyDe,c-eqsnuttraluyn,tcittsautrtriuvaceltusrrtearqluucrteiurqreuemi-raeecmtnivtesinttysforfreolraetfeifofifinccsiieheninptts II(nnQhhSAAARini)nhmhibieibttohitroosdrshs,ahvheoalvobegereabnmeeevnQaSleuAvaRtaeld(uHabQtyeSdA2DRb-)yaann2ddD- and 3D-quacnomtitpaatriavteivestmruocletucurlea-racfiteilvditaynarleylsaistio(CnosMhiFpAs) ([Q14S].ART)hemseesthtuoddiess, ihnodliocagtreadmthaQt SaApRote(HntQInShAAR) and compairnahtiibvietormsoholeucldulbaer afireelldativaenlayllyosnigs m(CooleMcuFleA, w) h[1ic4h].biTnhdsestoe tshteuIdniheAs ninexdtictoattehde NthAaDtHa cpofoatcetonrt InhA inhibitboirndshinoguslidte.bTehaisrienlhaitbiivtoerlyshloounldg amlsolceocnutlaein, wa bhuiclkhybgirnodups thoathseleIcnthivAelynfietxstintototahehyNdrAopDhHobcicofactor bindinpgoscikteet. E 2C), conformation of the NADH in these ternary complexes is extended, similar to the NADH conformation in the reference binary InhA-cofactor complex (PDB entry 4DRE [15]), Figure 3. NNAADDHHcoconnfoformrmataitoionnaanndd 22DD-d-deeppicictitoionn ooff ccooffaaccttoorr--IInnhhAA iinntteerraaccttiioonnss iinn tthhee ccrryyssttaall ssttrruuccttuurree 44DDRREE. The best InhA inhibitor designed so far belongs to the pyrrolidine carboxamide family (PCAM) and dTihspe lbaeysstaInnhinAhiinbhitiobriytocrodnecseingtnreadtiosno IfCar50boeflo3n90gsntMo t[h1e2]p. ABnacseedthoenvtahnedceormWpaleaxlsatiinotnerQacStAioRnsminodthelewheydwreorpehaobbliectpoopcrkeedtiocft tthhee IanchtiAvitbieinsdoifntghseitdee.sBiganseedd oPnCAthMe caonmalpolgeuxaetsioanndQsSeAleRctmthoedbeleswt eanwaeloreguabeslewtoithprtehdeichtigthheesatcptirveidtiiecsteodf tinhehidbeitsoirgynepdotPeCnAcieMs. aFnianlaolglyu,eAs aDnMdEseplercotfitlhese boef stthaenbaelosgt-udeessiwgnitehdthaenahliogghueesst pwreerdeicetestdiminahteibditaonrdy pcoomtepnacrieesd. Podreefleirnenocredewratso gidiveenntiftyo aannaalloogguueess wsuhbiscthitcuatnedfiot nintthoethbeenmzyecnoebraicntgersiaolaIns htoAebnihnadninceg tshitee.vParnefdeerrenWceaawlsasingtievreancttioonasnainlotghueehsysdubrosptihtuotbeidc opnoctkheetboefntzheenIenhriAngbsinodaisntgoseitneh. aBnacseedthoenvtahnedceormWpaleaxlsatiinotnerQacStAioRnsminodthelewheydwreorpehaobbliectpoopcrkeedtiocft tthhee IanchtiAvitbieinsdoifntghseitdee.sBiganseedd oPnCAthMe caonmalpolgeuxaetsioanndQsSeAleRctmthoedbeleswt eanwaeloreguabeslewtoithprtehdeichtigthheesatcptirveidtiiecsteodf tinhehidbeitsoirgynepdotPeCnAcieMs. aFnianlaolglyu,eAs aDnMdEseplercotfitlhese boef stthaenbaelosgt-udeessiwgnitehdthaenahliogghueesst pwreerdeicetestdiminahteibditaonrdy pcoomtepnacrieesd. wFiinthaltlhy,oAseDoMf tEhepraonfitilteusboefrtchuelobteicstd-druegsisgcnuerdreanntalylougsueedsiwn ethree ecslitnimicaaltepdraacntdicec.ompared with those of the antituberculotic drugs currently used in the clinical practice
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