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Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP).

Rackham MD, Brannigan JA, Rangachari K, Meister S, Wilkinson AJ, Holder AA, Leatherbarrow RJ, Tate EW - J. Med. Chem. (2014)

Bottom Line: N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria.Here we describe the discovery of 34c through optimization of a previously described series.Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.

ABSTRACT
N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

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Binding mode of 34a (pink) bound to PvNMT.(A) 34a (pink) forms all previously observed interactionswith the enzyme. (B) Comparison of the binding modes of 34a and 34c reaffirms this similarity, showing that theonly point of differentiation is in the Phe105/Ser319 binding siteoccupied by the pyrazole. (C) Enlarged view of the 1,3,5-trimethylpyrazoleof 34c (gold) and 3,5-dimethylpyrazole of 34a (pink) with PvNMT (green). The pyrazole of 34a formsa direct interaction with Ser319 (3.2 Å), and the water involvedin the bridged interaction in Figure 4B hasbeen excluded from the pocket.
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fig5: Binding mode of 34a (pink) bound to PvNMT.(A) 34a (pink) forms all previously observed interactionswith the enzyme. (B) Comparison of the binding modes of 34a and 34c reaffirms this similarity, showing that theonly point of differentiation is in the Phe105/Ser319 binding siteoccupied by the pyrazole. (C) Enlarged view of the 1,3,5-trimethylpyrazoleof 34c (gold) and 3,5-dimethylpyrazole of 34a (pink) with PvNMT (green). The pyrazole of 34a formsa direct interaction with Ser319 (3.2 Å), and the water involvedin the bridged interaction in Figure 4B hasbeen excluded from the pocket.

Mentions: The binding mode of 34a in PvNMT wasalso determined by crystallography (Figure 5A, PDB entry 4CAF). This compound displays a ∼40-fold lower binding affinityto PvNMT than 34c; however, the binding modes of thesetwo compounds are extremely similar (Figure 5B). The only point of differentiation is the pyrazole heterocyclewhich forms a direct polar interaction with Ser319 as opposed to thewater-bridged interaction observed in Figure 4B. Indeed, this water molecule is excluded from the pocket occupiedby 34a, perhaps indicating that it is involved in stabilizingSer319 and therefore that its expulsion to the bulk solvent is energeticallyunfavorable.


Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP).

Rackham MD, Brannigan JA, Rangachari K, Meister S, Wilkinson AJ, Holder AA, Leatherbarrow RJ, Tate EW - J. Med. Chem. (2014)

Binding mode of 34a (pink) bound to PvNMT.(A) 34a (pink) forms all previously observed interactionswith the enzyme. (B) Comparison of the binding modes of 34a and 34c reaffirms this similarity, showing that theonly point of differentiation is in the Phe105/Ser319 binding siteoccupied by the pyrazole. (C) Enlarged view of the 1,3,5-trimethylpyrazoleof 34c (gold) and 3,5-dimethylpyrazole of 34a (pink) with PvNMT (green). The pyrazole of 34a formsa direct interaction with Ser319 (3.2 Å), and the water involvedin the bridged interaction in Figure 4B hasbeen excluded from the pocket.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048319&req=5

fig5: Binding mode of 34a (pink) bound to PvNMT.(A) 34a (pink) forms all previously observed interactionswith the enzyme. (B) Comparison of the binding modes of 34a and 34c reaffirms this similarity, showing that theonly point of differentiation is in the Phe105/Ser319 binding siteoccupied by the pyrazole. (C) Enlarged view of the 1,3,5-trimethylpyrazoleof 34c (gold) and 3,5-dimethylpyrazole of 34a (pink) with PvNMT (green). The pyrazole of 34a formsa direct interaction with Ser319 (3.2 Å), and the water involvedin the bridged interaction in Figure 4B hasbeen excluded from the pocket.
Mentions: The binding mode of 34a in PvNMT wasalso determined by crystallography (Figure 5A, PDB entry 4CAF). This compound displays a ∼40-fold lower binding affinityto PvNMT than 34c; however, the binding modes of thesetwo compounds are extremely similar (Figure 5B). The only point of differentiation is the pyrazole heterocyclewhich forms a direct polar interaction with Ser319 as opposed to thewater-bridged interaction observed in Figure 4B. Indeed, this water molecule is excluded from the pocket occupiedby 34a, perhaps indicating that it is involved in stabilizingSer319 and therefore that its expulsion to the bulk solvent is energeticallyunfavorable.

Bottom Line: N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria.Here we describe the discovery of 34c through optimization of a previously described series.Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.

ABSTRACT
N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

Show MeSH
Related in: MedlinePlus