Deep Learning Enhancing Kinome-Wide Polypharmacology Profiling: Model Construction and Experiment Validation.

Abstract:

:The kinome-wide virtual profiling of small molecules with high-dimensional structure-activity data is a challenging task in drug discovery. Here, we present a virtual profiling model against a panel of 391 kinases based on large-scale bioactivity data and the multitask deep neural network algorithm. The obtained model yields excellent internal prediction capability with an auROC of 0.90 and consistently outperforms conventional single-task models on external tests, especially for kinases with insufficient activity data. Moreover, more rigorous experimental validations including 1410 kinase-compound pairs showed a high-quality average auROC of 0.75 and confirmed many novel predicted "off-target" activities. Given the verified generalizability, the model was further applied to various scenarios for depicting the kinome-wide selectivity and the association with certain diseases. Overall, the computational model enables us to create a comprehensive kinome interaction network for designing novel chemical modulators or drug repositioning and is of practical value for exploring previously less studied kinases.

journal_name

J Med Chem

authors

Li X,Li Z,Wu X,Xiong Z,Yang T,Fu Z,Liu X,Tan X,Zhong F,Wan X,Wang D,Ding X,Yang R,Hou H,Li C,Liu H,Chen K,Jiang H,Zheng M

doi

10.1021/acs.jmedchem.9b00855

subject

Has Abstract

pub_date

2020-08-27 00:00:00

pages

8723-8737

issue

16

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章
  • Computational studies on tetrahydropyrimidine-2-one HIV-1 protease inhibitors: improving three-dimensional quantitative structure-activity relationship comparative molecular field analysis models by inclusion of calculated inhibitor- and receptor-based pr

    abstract::A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar b...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm010417v

    authors: Nair AC,Jayatilleke P,Wang X,Miertus S,Welsh WJ

    更新日期:2002-02-14 00:00:00

  • Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses.

    abstract::Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound als...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm901230r

    authors: Su DS,Lim JJ,Tinney E,Wan BL,Young MB,Anderson KD,Rudd D,Munshi V,Bahnck C,Felock PJ,Lu M,Lai MT,Touch S,Moyer G,DiStefano DJ,Flynn JA,Liang Y,Sanchez R,Perlow-Poehnelt R,Miller M,Vacca JP,Williams TM,Anthony

    更新日期:2009-11-26 00:00:00

  • Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.

    abstract::A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this comp...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm980077m

    authors: Wong WC,Chiu G,Wetzel JM,Marzabadi MR,Nagarathnam D,Wang D,Fang J,Miao SW,Hong X,Forray C,Vaysse PJ,Branchek TA,Gluchowski C,Tang R,Lepor H

    更新日期:1998-07-02 00:00:00

  • Novel chemical space exploration via natural products.

    abstract::Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notably in coverage...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm801514w

    authors: Rosén J,Gottfries J,Muresan S,Backlund A,Oprea TI

    更新日期:2009-04-09 00:00:00

  • Modulating retinoid X receptor with a series of (E)-3-[4-hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic acids and their 4-alkoxy isomers.

    abstract::Rexinoids are ligands for the retinoid X receptor (RXR) that have great promise for both the prevention and treatment of cancer and metabolic diseases. In this regard, synthetic, functional, and structural investigations into the structure-activity relationships of derivatives of the potent RXR agonist (E)-3-[3-(3,5,5...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm900096q

    authors: Pérez Santín E,Germain P,Quillard F,Khanwalkar H,Rodríguez-Barrios F,Gronemeyer H,de Lera AR,Bourguet W

    更新日期:2009-05-28 00:00:00

  • Avermectin acyl derivatives with anthelmintic activity.

    abstract::Avermectins A2a, B1a, and B2a (1, 2, and 3) were acetylated to give 4"- and 23-acetates 4 and 5 and 4",23-diacetate 6 from 1, the 4"-and 5-acetates 7 and 8 and 4",5-diacetate 9 from 2, and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation c...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00348a010

    authors: Mrozik H,Eskola P,Fisher MH,Egerton JR,Cifelli S,Ostlind DA

    更新日期:1982-06-01 00:00:00

  • A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers.

    abstract::Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal ce...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm4012438

    authors: Millard M,Gallagher JD,Olenyuk BZ,Neamati N

    更新日期:2013-11-27 00:00:00

  • Synthesis of (R)-(-)- and (S)-(+)-4-fluorodeprenyl and (R)-(-)- and (S)-(+)-[N-11C-methyl]-4-fluorodeprenyl and positron emission tomography studies in baboon brain.

    abstract::(R)-(-)- and (S)-(+)-alpha-methyl-beta-4-(fluorophenyl)-N-methyl-N- propynylethylamine [R)-(-)- and (S)-(+)-4-fluorodeprenyl) were synthesized via the reaction of 4-fluorobenzaldehyde with nitroethane followed by reduction with lithium aluminum hydride to produce racemic 4-fluoroamphetamine, which was resolved by recr...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00169a034

    authors: Plenevaux A,Dewey SL,Fowler JS,Guillaume M,Wolf AP

    更新日期:1990-07-01 00:00:00

  • Structure-activity relationships of imidazo[4,5-f]quinoline partial structures and analogs. Discovery of pyrazolo[3,4-f]quinoline derivatives as potent immunostimulants.

    abstract::Structure-activity studies have been carried out on a series of imidazo[4,5-f]quinoline derivatives reported to have potent in vivo immunostimulatory activity. This activity has been confirmed, and subtle structure-activity relationships have been uncovered which resulted in the identification of novel analogs (pyrazo...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00102a013

    authors: Moyer MP,Weber FH,Gross JL

    更新日期:1992-11-27 00:00:00

  • Synthesis and anticancer activity comparison of phenylalkyl isoselenocyanates with corresponding naturally occurring and synthetic isothiocyanates.

    abstract::Synthesis and identification of novel phenylalkyl isoselenocyanates (ISCs), isosteric selenium analogues of naturally occurring phenylalkyl isothiocyanates (ITCs), as effective cytotoxic and antitumor agents are described. The structure-activity relationship comparison of ISCs with ITCs and effect of the increasing al...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm800993r

    authors: Sharma AK,Sharma A,Desai D,Madhunapantula SV,Huh SJ,Robertson GP,Amin S

    更新日期:2008-12-25 00:00:00

  • Theoretical model-based equations for the linear free energy relationships of the biological activity of ionizable substances. 1. Equilibrium-controlled potency.

    abstract::Because of the ambiguities of how to treat ionization in empirical equations which relate biological activity to partition coefficient by use of a (log P)2 term, a theoretical approach to the problem is proposed. Based on a simplified view of assays of potency following in vitro or continuous infusion administration o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00230a012

    authors: Martin YC,Hackbarth JJ

    更新日期:1976-08-01 00:00:00

  • Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule.

    abstract::Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.7b00324

    authors: Cheng X,Merz KH,Vatter S,Zeller J,Muehlbeyer S,Thommet A,Christ J,Wölfl S,Eisenbrand G

    更新日期:2017-06-22 00:00:00

  • Identification of diarylsulfone sulfonamides as secreted frizzled related protein-1 (sFRP-1) inhibitors.

    abstract::Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm801069w

    authors: Gopalsamy A,Shi M,Stauffer B,Bahat R,Billiard J,Ponce-de-Leon H,Seestaller-Wehr L,Fukayama S,Mangine A,Moran R,Krishnamurthy G,Bodine P

    更新日期:2008-12-25 00:00:00

  • Apstatin analogue inhibitors of aminopeptidase P, a bradykinin-degrading enzyme.

    abstract::Membrane-bound aminopeptidase P (AP-P) participates in the degradation of bradykinin in several vascular beds. We have developed an inhibitor of AP-P called apstatin (1) (N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]-L-prolyl-L-prolyl-L-al aninam ide); IC50,human = 2.9 microM. In the rat, apstatin can potentiate th...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm9805642

    authors: Maggiora LL,Orawski AT,Simmons WH

    更新日期:1999-07-01 00:00:00

  • Fishing for Drug Targets: A Focus on Diazirine Photoaffinity Probe Synthesis.

    abstract::Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient molecular interactions. This can help identify target proteins and map the ligand's interactome. Diazirine probes have even be...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1021/acs.jmedchem.7b01561

    authors: Hill JR,Robertson AAB

    更新日期:2018-08-23 00:00:00

  • Crystal structures of HLA-A*0201 complexed with Melan-A/MART-1(26(27L)-35) peptidomimetics reveal conformational heterogeneity and highlight degeneracy of T cell recognition.

    abstract::There is growing interest in using tumor associated antigens presented by class I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrat...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm100683p

    authors: Douat-Casassus C,Borbulevych O,Tarbe M,Gervois N,Jotereau F,Baker BM,Quideau S

    更新日期:2010-10-14 00:00:00

  • Recognition of privileged structures by G-protein coupled receptors.

    abstract::Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm0309452

    authors: Bondensgaard K,Ankersen M,Thøgersen H,Hansen BS,Wulff BS,Bywater RP

    更新日期:2004-02-12 00:00:00

  • Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids.

    abstract::Analogues of 9-oxo-9H-xanthene-4-acetic acid (XAA) bearing small, lipophilic 5-substituents are among the most dose-potent compounds yet reported with the capability of causing hemorrhagic necrosis of implanted colon 38 tumors in mice. To further extend structure-activity relationships among this class of compound, a ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00105a034

    authors: Rewcastle GW,Atwell GJ,Li ZA,Baguley BC,Denny WA

    更新日期:1991-01-01 00:00:00

  • Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors.

    abstract::The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suita...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm960582o

    authors: Ksander GM,de Jesus R,Yuan A,Ghai RD,Trapani A,McMartin C,Bohacek R

    更新日期:1997-02-14 00:00:00

  • Synthesis and biological evaluation of novel 1-deoxy-1-[6-[((hetero)arylcarbonyl)hydrazino]- 9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamide derivatives as useful templates for the development of A2B adenosine receptor agonists.

    abstract::The lack of molecules endowed with selective and potent agonistic activity toward the hA2B adenosine receptors has limited the studies on this pharmacological target and consequently the evaluation of its therapeutic potential. We report the design and the synthesis of the first potent (EC50 in the nanomolar range) an...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm061170a

    authors: Baraldi PG,Preti D,Tabrizi MA,Fruttarolo F,Romagnoli R,Carrion MD,Cara LC,Moorman AR,Varani K,Borea PA

    更新日期:2007-01-25 00:00:00

  • Microwave-assisted ring opening of epoxides: a general route to the synthesis of 1-aminopropan-2-ols with anti malaria parasite activities.

    abstract::A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening of epoxides (aryl and alkyl glycidyl ethers, glycidol, epichlorohydrin) with various amines without catalyst...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm070553l

    authors: Robin A,Brown F,Bahamontes-Rosa N,Wu B,Beitz E,Kun JF,Flitsch SL

    更新日期:2007-08-23 00:00:00

  • Synthesis and Structure-Activity Relationship Studies of C2-Modified Analogs of the Antimycobacterial Natural Product Pyridomycin.

    abstract::A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of suffic...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.9b01457

    authors: Kienle M,Eisenring P,Stoessel B,Horlacher OP,Hasler S,van Colen G,Hartkoorn RC,Vocat A,Cole ST,Altmann KH

    更新日期:2020-02-13 00:00:00

  • Designing allosteric regulators of thrombin. Exosite 2 features multiple subsites that can be targeted by sulfated small molecules for inducing inhibition.

    abstract::We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. A...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm400369q

    authors: Sidhu PS,Abdel Aziz MH,Sarkar A,Mehta AY,Zhou Q,Desai UR

    更新日期:2013-06-27 00:00:00

  • Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A.

    abstract::A series of balanol analogs in which the perhydroazepine ring and the p-hydroxybenzamide moiety were combined into an acyclic linked unit have been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to low-nanomolar inhibitors of the alpha, beta I, be...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm960581w

    authors: Defauw JM,Murphy MM,Jagdmann GE Jr,Hu H,Lampe JW,Hollinshead SP,Mitchell TJ,Crane HM,Heerding JM,Mendoza JS,Davis JE,Darges JW,Hubbard FR,Hall SE

    更新日期:1996-12-20 00:00:00

  • 3-substituted indole inhibitors against Francisella tularensis FabI identified by structure-based virtual screening.

    abstract::In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bou...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm4001242

    authors: Hu X,Compton JR,Abdulhameed MD,Marchand CL,Robertson KL,Leary DH,Jadhav A,Hershfield JR,Wallqvist A,Friedlander AM,Legler PM

    更新日期:2013-07-11 00:00:00

  • Dipeptidyl peptidase IV dependent water-soluble prodrugs of highly lipophilic bicyclic nucleoside analogues.

    abstract::We present the first report of the application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to hydroxy-containing drug derivatives. In particular, we applied this strategy to the highly lipophilic antiviral drug family of bicyclic furanopyrimidine nucleoside analogues (BCNA) in order to improve t...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm101624e

    authors: Diez-Torrubia A,Balzarini J,Andrei G,Snoeck R,De Meester I,Camarasa MJ,Velázquez S

    更新日期:2011-03-24 00:00:00

  • Structure-guided design of A(3) adenosine receptor-selective nucleosides: combination of 2-arylethynyl and bicyclo[3.1.0]hexane substitutions.

    abstract::(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analo...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm300396n

    authors: Tosh DK,Deflorian F,Phan K,Gao ZG,Wan TC,Gizewski E,Auchampach JA,Jacobson KA

    更新日期:2012-05-24 00:00:00

  • Synthesis and structure-activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors.

    abstract::A series of UTP, UDP, and UMP derivatives and analogues were synthesized and evaluated at the human pyrimidinergic P2Y receptor subtypes P2Y2, P2Y4, and P2Y6 stably expressed in 1321N1 astrocytoma cells. Substituents at N3 of UTP were poorly tolerated by P2Y2 and P2Y4 receptors. In contrast, a large phenacyl substitue...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm060848j

    authors: El-Tayeb A,Qi A,Müller CE

    更新日期:2006-11-30 00:00:00

  • The enantiomeric specificity of the antihypertensive activity of 1-(phenylthio)-2-aminopropane, a synthetic substrate analogue for dopamine beta-monooxygenase.

    abstract::We have found that (R,S)-1-(phenylthio)-aminopropane (4a), a synthetic alternate substrate for the terminal enzyme of norepinephrine biosynthesis, dopamine beta-monooxygenase (DBM), is both an indirect sympathomimetic and a potent antihypertensive agent in spontaneously hypertensive rats. We demonstrate herein that th...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00107a031

    authors: Herman HH,Husain PA,Colbert JE,Schweri MM,Pollock SH,Fowler LC,May SW

    更新日期:1991-03-01 00:00:00

  • Nucleosides and nucleotides. 200. Reinvestigation of 5'-N-ethylcarboxamidoadenosine derivatives: structure-activity relationships for P(3) purinoceptor-like proteins.

    abstract::The non-P(1) and non-P(2) muscle relaxant effect of ATP in rabbit thoracic aorta has recently been attributed to a putative P(3) purinoceptor, which is activated by either adenosine or ATP. Since the physiological roles of this putative P(3) purinoceptor and of a new [(3)H]-5'-N-ethylcarboxamidoadenosine (NECA)-bindin...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm000150k

    authors: Umino T,Yoshioka K,Saitoh Y,Minakawa N,Nakata H,Matsuda A

    更新日期:2001-01-18 00:00:00