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–S14
7. Reickmann KH (1973) Chemotherapy of malaria and resistance to antimalarials. World
Health Organization technical report, vol 529. World Health Organisation, Geneva
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:
16823–16828
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) Shapeand chemical feature-based 3D-pharmacophore model generation and virtual screening:
identification of potential leads for P. falciparum DHFR enzyme inhibition. Chem Biol Drug
Des 75:115–126
10. Mehdi A, Adane L, Patel DS, Bharatam PV (2010) Electronic structure and reactivity of
guanylthiourea: a quantum chemical study. J Comput Chem 31:1259–1267
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
33:1913–1928
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 135:339–348
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 57:2524–2535
14. Corbett KD, Berger JM (2010) Structure of the ATP-binding domain of Plasmodium
falciparum Hsp90. Proteins 78:2738–2744
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
53:3552–3557
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 2:30
17. Posfai D, Eubanks AL et al. (2018) Identification of Hsp90 inhibitors with anti-plasmodium
activity. Antimicrob Agents Chemother 62:e01799–01717
18. Krüger T, Sanchez CP, Lanzer M (2010) Complementation of Saccharomyces cerevisiae
pik1
ts by a phosphatidylinositol 4-kinase from Plasmodium falciparum. Mol Biochem
Parasitol 172:149–151
19. Rajkhowa S, Borah SM, Jha AN, Deka RC (2017) Design of Plasmodium falciparum PI(4)
KIIIb inhibitor using molecular dynamics and molecular docking methods. ChemistrySelect
2:1783–1792
216
S. Bhagat et al.
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–S14
7. Reickmann KH (1973) Chemotherapy of malaria and resistance to antimalarials. World
Health Organization technical report, vol 529. World Health Organisation, Geneva
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:
16823–16828
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) Shapeand chemical feature-based 3D-pharmacophore model generation and virtual screening:
identification of potential leads for P. falciparum DHFR enzyme inhibition. Chem Biol Drug
Des 75:115–126
10. Mehdi A, Adane L, Patel DS, Bharatam PV (2010) Electronic structure and reactivity of
guanylthiourea: a quantum chemical study. J Comput Chem 31:1259–1267
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
33:1913–1928
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 135:339–348
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 57:2524–2535
14. Corbett KD, Berger JM (2010) Structure of the ATP-binding domain of Plasmodium
falciparum Hsp90. Proteins 78:2738–2744
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
53:3552–3557
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 2:30
17. Posfai D, Eubanks AL et al. (2018) Identification of Hsp90 inhibitors with anti-plasmodium
activity. Antimicrob Agents Chemother 62:e01799–01717
18. Krüger T, Sanchez CP, Lanzer M (2010) Complementation of Saccharomyces cerevisiae
pik1
ts by a phosphatidylinositol 4-kinase from Plasmodium falciparum. Mol Biochem
Parasitol 172:149–151
19. Rajkhowa S, Borah SM, Jha AN, Deka RC (2017) Design of Plasmodium falciparum PI(4)
KIIIb inhibitor using molecular dynamics and molecular docking methods. ChemistrySelect
2:1783–1792
216
S. Bhagat et al.