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Structure-Based Drug Design of PfDHODH Inhibitors as Antimalarial Agents

  • Shweta Bhagat
  • Anuj Gahlawat
  • Prasad V. Bharatam
Chapter
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 27)

Abstract

Structure-based drug design (SBDD) is being efficiently used for the design of antimalarial agents. It is a very effective tool for challenges like drug selectivity and resistance. Over the past decade, a considerable number of druggable targets have been explored—these include Na+ ATPase 4 ion channel, cytochrome bc1, mitochondrial electron transport chain, phosphatidylinositol 4-kinase (PfPI4 K), dihydroorotate dehydrogenase, hemozoin formation, dihydrofolate reductase inhibitors, etc. Among these, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a new and very promising target. PfDHODH has shown considerable potential in arresting growth of the parasite at blood stage by inhibiting pyrimidine biosynthesis. This chapter provides a review of all the SBDD efforts for the development of inhibitors against PfDHODH.

Keywords

Plasmodium falciparum Structure-based drug design Molecular docking Virtual screening Dihydroorotate dehydrogenase Selectivity 

List of Abbreviations

ACT

Aspartate carbamoyltransferase

ADME

Absorption, distribution, metabolism, and excretion

CoMFA

Comparative molecular field analysis

CoMSIA

Comparative molecular similarity index analysis

CoQ

Coenzyme Q (Ubiquinone)

CTP

Cytidine triphosphate

DBP

Docking-based pharmacophore

DHOtase

Dihydroorotase

DHO

Dihydroorotate

DHODH

Dihydroorotate dehydrogenase

dTMP

Deoxyribose thymidine monophosphate

E. coli.

Escherichia coli

FAD

Flavin adenine dinucleotide

FMN

Flavin mononucleotide

G/PLS

Genetic partial least squares

GAT/CPS

Glutamine amidotransferase/carbamoyl phosphate synthetase

m-

meta-

MM/GBSA

Molecular mechanics/Generalized Born surface area

MSA

Molecular shape analysis

MLR

Multilinear regression

NAD

Nicotinamide adenine dinucleotide

OMPDC

Orotidine 5′-monophosphate decarboxylase

OPRT

Orotate phosphoribosyltransferase

ORO

Orotate

o-

ortho-

p-

para-

Pb

Plasmodium berghei

PDB

Protein Data Bank

Pf

Plasmodium falciparum

PRPP

Phosphoribosylpyrophosphate

QSAR

Quantitative structure–activity relationship

RMS

Root mean square

RNA

Ribonucleic Acid

SBDD

Structure-based drug design

SVM

Support vector machine

UMP

Uridine monophosphate

UTP

Uridine triphosphate

Notes

Acknowledgements

The University Grants Commission is gratefully acknowledged for the financial support to Shweta Bhagat (UGC, Grant No. 43395). The authors thank Department of Science and Technology (DST), Government of India, New Delhi, India, for financial support.

References

  1. 1.
    World Malaria Report (2017) World Health Organization, Geneva. doi: ISBN 978-92-4-156552-3Google Scholar
  2. 2.
    [a] Gregson A, Plowe CV (2005) Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57:117–145; [b] Harinasuta T, Suntharasamai P, Viravan C (1965) Chloroquine-resistant falciparum malaria in Thailand. The Lancet 2:657–660; [c] Sirawaraporn W, Prapunwattana P et al. (1993) The dihydrofolate reductase domain of Plasmodium falciparum thymidylate synthase-dihydrofolate reductase. Gene synthesis, expression, and anti-folate-resistant mutants. J Biol Chem 268:21637–21644Google Scholar
  3. 3.
    Wells TNC, van Huijsduijnen RH, Van Voorhis WC (2015) Malaria medicines: a glass half full? Nat Rev Drug Discov 14:424–442PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Tinto H, D’Alessandro U et al (2015) Efficacy and safety of RTS, S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. The Lancet 386:31–45CrossRefGoogle Scholar
  5. 5.
    Anderson AC (2003) The process of structure-based drug design. Chem Biol 10:787–797PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    [a] Cowman AF, Morry MJ et al. (1988) Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 85:9109–9113; [b] Foote SJ, Galatis D, Cowman AF (1990) Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum Involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci USA 87:3014–3017; [c] Peterson DS, Milhous WK, Wellems TE (1990) Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum Malaria. Proc Natl Acad Sci USA 87:3018–3022; [d] Peterson DS, Walliker D, Wellems TE (1988) Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci USA 85:9114–9118; [e] Plowe CV (2009) The evolution of drug-resistant malaria. Trans R Soc Trop Med Hyg 103:S11–S14Google Scholar
  7. 7.
    Reickmann KH (1973) Chemotherapy of malaria and resistance to antimalarials. World Health Organization technical report, vol 529. World Health Organisation, GenevaGoogle Scholar
  8. 8.
    Yuthavong Y, Tarnchompoo B et al (2012) Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci U S A 109:16823–16828PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    [a] Adane L, Bharatam PV, Sharma V (2010) A common feature-based 3D-pharmacophore model generation and virtual screening: identification of potential PfDHFR inhibitors. J Enzyme Inhib Med Chem 25:635–645; [b] Adane L, Patel DS, Bharatam PV (2010) Shape- and chemical feature-based 3D-pharmacophore model generation and virtual screening: identification of potential leads for P. falciparum DHFR enzyme inhibition. Chem Biol Drug Des 75:115–126Google Scholar
  10. 10.
    Mehdi A, Adane L, Patel DS, Bharatam PV (2010) Electronic structure and reactivity of guanylthiourea: a quantum chemical study. J Comput Chem 31:1259–1267PubMedPubMedCentralGoogle Scholar
  11. 11.
    Abbat S, Jain V, Bharatam PV (2015) Origins of the specificity of inhibitor P218 toward wild-type and mutant PfDHFR: a molecular dynamics analysis. J Biomol Struct Dyn 33:1913–1928PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    [a] Adane L, Bhagat S et al. (2014) Design and synthesis of guanylthiourea derivatives as potential inhibitors of Plasmodium falciparum dihydrofolate reductase enzyme. Bioorg Med Chem Lett 24:613–617; [b] Bhagat S, Arfeen M et al. (2017) Guanylthiourea derivatives as potential antimalarial agents: synthesis, in vivo and molecular modelling studies. Eur J Med Chem 135:339–348Google Scholar
  13. 13.
    [a] Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Bio 11:515; [b] Wang T, Bisson WH et al. (2014) Differences in conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery of pathogen-selective inhibitors. J Med Chem 57:2524–2535Google Scholar
  14. 14.
    Corbett KD, Berger JM (2010) Structure of the ATP-binding domain of Plasmodium falciparum Hsp90. Proteins 78:2738–2744PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Shahinas D, Liang M, Datti A, Pillai DR (2010) A repurposing strategy identifies novel synergistic inhibitors of Plasmodium falciparum heat shock protein 90. J Med Chem 53:3552–3557PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Kumar R, Musiyenko A, Barik S (2003) The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin. Malar J 2:30PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Posfai D, Eubanks AL et al. (2018) Identification of Hsp90 inhibitors with anti-plasmodium activity. Antimicrob Agents Chemother 62:e01799–01717Google Scholar
  18. 18.
    Krüger T, Sanchez CP, Lanzer M (2010) Complementation of Saccharomyces cerevisiae pik1ts by a phosphatidylinositol 4-kinase from Plasmodium falciparum. Mol Biochem Parasitol 172:149–151PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Rajkhowa S, Borah SM, Jha AN, Deka RC (2017) Design of Plasmodium falciparum PI(4)KIIIβ inhibitor using molecular dynamics and molecular docking methods. ChemistrySelect 2:1783–1792CrossRefGoogle Scholar
  20. 20.
    McNamara CW, Lee MC et al (2013) Targeting Plasmodium PI(4)K to eliminate malaria. Nature 504:248–253PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Achieng AO, Rawat M et al (2017) Antimalarials: molecular drug targets and mechanism of action. Curr Top Med Chem 17:2114–2128PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Melo AM, Bandeiras TM, Teixeira M (2004) New insights into type II NAD (P) H: quinone oxidoreductases. Microbiol Mol Biol Rev 68:603–616PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Biagini GA, Viriyavejakul P et al (2006) Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria. Antimicrob Agents Chemother 50:1841–1851PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Pidathala C, Amewu R et al (2012) Identification, design and biological evaluation of bisaryl quinolones targeting Plasmodium falciparum type II NADH: quinone oxidoreductase (PfNDH2). J Med Chem 55:1831–1843PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Yang Y, Yu Y et al (2017) Target elucidation by cocrystal structures of NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) with small molecule to eliminate drug-resistant malaria. J Med Chem 60:1994–2005PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Rodrigues T, Lopes F, Moreira R (2010) Inhibitors of the mitochondrial electron transport chain and de novo pyrimidine biosynthesis as antimalarials: the present status. Curr Med Chem 17:929–956PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Alnabulsi S, Santina E et al (2016) Non-symmetrical furan-amidines as novel leads for the treatment of cancer and malaria. Eur J Med Chem 111:33–45PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Banerjee AK, Arora N, Murty USN (2012) Aspartate carbamoyltransferase of Plasmodium falciparum as a potential drug target for designing anti-malarial chemotherapeutic agents. Med Chem Res 21:2480–2493CrossRefGoogle Scholar
  29. 29.
    [a] Lunev S, Bosch SS et al. (2016) Crystal structure of truncated aspartate transcarbamoylase from Plasmodium falciparum. Acta Crystallogr F 72:523–533; [b] Lunev S, Bosch SS et al. (2018) Identification of a non-competitive Inhibitor of Plasmodium falciparum aspartate transcarbamoylase. Biochem Biophys Res Commun 497:835–842Google Scholar
  30. 30.
    Fritz-Wolf K, Jortzik E et al (2013) Crystal structure of the Plasmodium falciparum thioredoxin reductase-thioredoxin complex. J Mol Biol 425:3446–3460PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    McMillan PJ, Arscott LD et al (2006) Identification of acid-base catalytic residues of high-Mr thioredoxin reductase from Plasmodium falciparum. J Biol Chem 281:32967–32977PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Boumis G, Giardina G et al (2012) Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target. Biochem Biophys Res Commun 425:806–811PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    McCarty SE, Schellenberger A et al (2015) Plasmodium falciparum thioredoxin reductase (PfTrxR) and its role as a target for new antimalarial discovery. Molecules 20:11459–11473PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Munigunti R, Gathiaka S et al (2013) Characterization of PfTrxR inhibitors using antimalarial assays and in silico techniques. Chem Cent J 7:175PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Munigunti R, Gathiaka S et al (2014) Determination of antiplasmodial activity and binding affinity of curcumin and demethoxycurcumin towards PfTrxR. Nat Prod Res 28:359–364PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Winkler M, Maynadier M et al (2015) Uncovering new structural insights for antimalarial activity from cost-effective aculeatin-like derivatives. Org Biomol Chem 13:2064–2077PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Chaal BK, Gupta AP et al (2010) Histone deacetylases play a major role in the transcriptional regulation of the Plasmodium falciparum life cycle. PLoS Path 6:e1000737CrossRefGoogle Scholar
  38. 38.
    [a] Gupta AP, Bozdech Z (2017) Epigenetic landscapes underlining global patterns of gene expression in the human malaria parasite, Plasmodium falciparum. Int J Parasitol 47:399–407; [b] Sumanadasa SDM, Goodman CD et al. (2012) Antimalarial activity of the anticancer histone deacetylase inhibitor SB939. Antimicrob Agents Chemother 56:3849–3856Google Scholar
  39. 39.
    Mukherjee P, Pradhan A et al (2008) Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): a novel target for the development of antimalarial therapy. Bioorg Med Chem 16:5254–5265PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Hansen FK, Sumanadasa SDM et al. Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages. Eur J Med Chem 82:204–213PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Darkin-Rattray SJ, Gurnett AM et al (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 93:13143–13147PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Harwaldt P, Rahlfs S, Becker K (2002) Glutathione S-transferase of the malarial parasite Plasmodium falciparum: characterization of a potential drug target. Biol Chem 383:821–830PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Hiller N, Fritz-Wolf K et al (2006) Plasmodium falciparum glutathione S-transferase—structural and mechanistic studies on ligand binding and enzyme inhibition. Protein Sci 15:281–289PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Fritz-Wolf K, Becker A et al (2003) X-ray structure of glutathione S-transferase from the malarial parasite Plasmodium falciparum. Proc Natl Acad Sci USA 100:13821–13826PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Perbandt M, Eberle R et al (2015) High resolution structures of Plasmodium falciparum GST complexes provide novel insights into the dimer-tetramer transition and a novel ligand-binding site. J Struct Biol 191:365–375PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Ahmad R, Srivastava AK (2008) Inhibition of glutathione-S-transferase from Plasmodium yoelii by protoporphyrin IX, cibacron blue and menadione: implications and therapeutic benefits. Parasitol Res 102:805–807PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Miller RW, Kerr CT, Curry JR (1968) Mammalian dihydroorotate—ubiquinone reductase complex. Can J Biochem 46:1099–1106PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Chen JJ, Jones ME (1976) The cellular location of dihydroorotate dehydrogenase: relation to de novo biosynthesis of pyrimidines. Arch Biochem Biophys 176:82–90PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    [a] Larsen JN, Jensen KF (1985) Nucleotide sequence of the pyrD gene of Escherichia coli and characterization of the flavoprotein dihydroorotate dehydrogenase. Eur J Biochem 151:59–65; [b] LeBlanc SB, Wilson CM (1993) The dihydroorotate dehydrogenase gene homologue of Plasmodium falciparum. Mol Biochem Parasitol 60:349–351PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    [a] Gardner MJ, Hall N et al. (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498–511; [b] K. Vyas V, Ghate M (2011) Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. Mini-Rev Med Chem 11:1039–1055Google Scholar
  51. 51.
    Krungkrai J (1995) Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. Biochim Biophys Acta Gen Subj 1243:351–360CrossRefGoogle Scholar
  52. 52.
    McRobert L, McConkey GA (2002) RNA Interference (RNAi) inhibits growth of Plasmodium falciparum. Mol Biochem Parasitol 119:273–278PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Baldwin J, Farajallah AM et al (2002) Malarial dihydroorotate dehydrogenase: substrate and inhibitor specificity. J Biol Chem 277:41827–41834PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Boa AN, Canavan SP et al (2005) Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase. Bioorg Med Chem 13:1945–1967PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Baldwin J, Michnoff CH et al (2005) High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem 280:21847–21853PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Heikkilä T, Thirumalairajan S et al (2006) The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett 16:88–92PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Phillips MA, Rathod PK (2010) Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets 10:226–239PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Löffler M, Fairbanks LD et al (2005) Pyrimidine pathways in health and disease. Trends Mol Med 11:430–437PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Fagan RL, Nelson MN, Pagano PM, Palfey BA (2006) Mechanism of flavin reduction in class 2 dihydroorotate dehydrogenases. Biochemistry 45:14926–14932PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Liu S, Neidhardt EA et al (2000) Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure 8:25–33PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Fagan RL, Palfey BA (2009) Roles in binding and chemistry for conserved active site residues in the class 2 dihydroorotate dehydrogenase from Escherichia coli. Biochemistry 48:7169–7178PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Hurt DE, Widom J, Clardy J (2006) Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta Crystallogr Sect D: Biol Crystallogr D62:312–323CrossRefGoogle Scholar
  63. 63.
    Drozdetskiy A, Cole C, Procter J, Barton GJ (2015) JPred4: a protein secondary structure prediction server. Nucleic Acids Res 43:W389–W394PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Deng X, Gujjar R et al (2009) Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J Biol Chem 284:26999–27009PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Booker ML, Bastos CM et al (2010) Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem 285:33054–33064PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Coteron JM, Marco M et al (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem 54:5540–5561PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ross LS, Gamo FJ et al (2014) In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug-binding site and altered growth. J Biol Chem 289:17980–17995PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Deng X, Kokkonda S et al (2014) Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J Med Chem 57:5381–5394PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Phillips MA, Lotharius J et al (2015) A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med 7:296ra111PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Deng X, Matthews D, Rathod PK, Phillips MA (2015) The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions. Acta Crystallogr Sec F 71:553–559CrossRefGoogle Scholar
  71. 71.
    Kokkonda S, Deng X et al (2016) Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidines targeting Plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity. J Med Chem 59:5416–5431PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Phillips MA, White KL et al (2016) A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect Dis 2:945–957PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Malmquist NA, Gujjar R, Rathod PK, Phillips MA (2008) Analysis of flavin oxidation and electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase. Biochemistry 47:2466–2475PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    [a] Norager S, Jensen KF, Björnberg O, Larsen S (2002) E. coli Dihydroorotate dehydrogenase reveals structural and functional distinctions between different classes of dihydroorotate dehydrogenases. structure 10:1211–1223; [b] Rowland P, Bjornberg O et al. (1998) The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A complexed with the enzyme reaction product throws light on its enzymatic function. Protein Sci 7:1269–1279; [c] Rowland P, Nielsen FS, Jensen KF, Larsen S (1997) The crystal structure of the flavin containing enzyme dihydroorotate dehydrogenase A from Lactococcus lactis. Structure 5:239–252; [d] Sørensen PG, Dandanell G (2002) A new type of dihydroorotate dehydrogenase, type 1S, from the thermoacidophilic archaeon Sulfolobus solfataricus. Extremophiles 6:245–251Google Scholar
  75. 75.
    Bedingfield PT, Cowen D et al (2012) Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases. J Med Chem 55:5841–5850PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Copeland RA, Davis JP et al (1995) Recombinant human dihydroorotate dehydrogenase: expression, purification, and characterization of a catalytically functional truncated enzyme. Arch Biochem Biophys 323:79–86PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    [a] Löffler M, Knecht W et al. (2002) Drosophila melanogaster dihydroorotate dehydrogenase: the N-terminus is important for biological function in vivo but not for catalytic properties in vitro. Insect Biochem Mol Biol 32:1159–1169; [b] Rawls J, Knecht W et al. (2000) Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase. Eur J Biochem 267:2079–2087Google Scholar
  78. 78.
    Phillips MA, Gujjar R et al (2008) Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. J Med Chem 51:3649–3653PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Heikkilä T, Ramsey C et al (2007) Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J Med Chem 50:186–191PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    [a] Patel V, Booker M et al. (2008) Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem 283:35078–35085; [b] Skerlj RT, Bastos CM et al. (2011) Optimization of potent inhibitors of P. falciparum dihydroorotate dehydrogenase for the treatment of malaria. ACS Med Chem Lett 2:708–713Google Scholar
  81. 81.
    Fritzson I, Bedingfield PTP et al (2011) N-substituted salicylamides as selective malaria parasite dihydroorotate dehydrogenase inhibitors. Med Chem Comm 2:895–898CrossRefGoogle Scholar
  82. 82.
    Zhu J, Han L et al (2015) Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase. J Med Chem 58:1123–1139PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Azeredo LFSP, Coutinho JP et al (2017) Evaluation of 7-arylaminopyrazolo [1,5-a] pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf dihydroorotate dehydrogenase inhibitors. Eur J Med Chem 126:72–83PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Xu M, Zhu J et al (2013) Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives. J Med Chem 56:7911–7924PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Schneider G, Fechner U (2005) Computer-based de novo design of drug-like molecules. Nat Rev Drug Discov 4:649PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Gillet VJ, Newell W et al (1994) SPROUT: recent developments in the de novo design of molecules. J Chem Inf Comput Sci 34:207–217PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Gujjar R, Marwaha A et al (2009) Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem 52:1864–1872PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Gujjar R, El Mazouni F et al (2011) Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium Falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. J Med Chem 54:3935–3949PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ojha PK, Roy K (2010) Chemometric modeling, docking and in silico design of triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors as antimalarials. Eur J Med Chem 45:4645–4656PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Shah P, Kumar S, Tiwari S, Siddiqi MI (2012) 3D-QSAR studies of triazolopyrimidine derivatives of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics, docking, and genetic algorithm-based methods. J Chem Biol 5:91–103PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Desai KR, Shaikh MS, Coutinho EC (2011) Molecular modeling studies, synthesis and biological evaluation of derivatives of N-phenylbenzamide as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Med Chem Res 20:321–332CrossRefGoogle Scholar
  92. 92.
    Vyas VK, Parikh H, Ghate M (2013) 3D QSAR studies on 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Med Chem Res 22:2235–2243CrossRefGoogle Scholar
  93. 93.
    Wadood A, Zaheer-ulhaqb (2013) In silico identification of novel inhibitors against Plasmodium falciparum dihydroorate dehydrogenase. J Mol Graphics Model 40:40–47CrossRefGoogle Scholar
  94. 94.
    Tseng TS, Lee YC et al (2016) Comparative study between 3D-QSAR and docking-based pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors. Bioorg Med Chem Lett 26:265–271PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Hou X, Chen X, Zhang M, Yan A (2016) QSAR study on the antimalarial activity of Plasmodium falciparum dihydroorotate dehydrogenase (Pf DHODH) inhibitors. SAR QSAR Environ Res 27:101–124PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Pavadai E, El Mazouni F et al (2016) Identification of new human malaria parasite Plasmodium falciparum dihydroorotate dehydrogenase inhibitors by pharmacophore and structure-based virtual screening. J Chem Inf Model 56:548–562PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Shweta Bhagat
    • 1
  • Anuj Gahlawat
    • 2
  • Prasad V. Bharatam
    • 1
  1. 1.Department of Medicinal ChemistryNational Institute of Pharmaceutical Education and Research (NIPER)S.A.S. NagarIndia
  2. 2.Department of PharmacoinformaticsNational Institute of Pharmaceutical Education and Research (NIPER)S.A.S. NagarIndia

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