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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 34c (gold) bound to PvNMT.(A) 34c (gold) bound to PvNMT (green), showing piperidine–Leu410salt bridge interaction, deeply buried benzothiophene scaffold, and1,3,5-trimethylpyrazole heterocycle bound within the Ser319 hydrophobicpocket. (B) Enlarged view of the 1,3,5-trimethylpyrazole of 34c (gold) with PvNMT (green). This shows the water-bridgedinteraction between the pyrazole and Ser319, as well as multiple hydrophobiccontacts between the heterocycle and the binding pocket.
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fig4: Binding mode of 34c (gold) bound to PvNMT.(A) 34c (gold) bound to PvNMT (green), showing piperidine–Leu410salt bridge interaction, deeply buried benzothiophene scaffold, and1,3,5-trimethylpyrazole heterocycle bound within the Ser319 hydrophobicpocket. (B) Enlarged view of the 1,3,5-trimethylpyrazole of 34c (gold) with PvNMT (green). This shows the water-bridgedinteraction between the pyrazole and Ser319, as well as multiple hydrophobiccontacts between the heterocycle and the binding pocket.

Mentions: The binding mode of 34c was elucidatedby crystallography, as briefly described previously20 (Figure 4, PDB entry 2YNE). As predicted during the compound design process, the pyrazoleof 34c does not directly interact with the target Ser319,indicating a subtler basis for the affinity improvement. The pyrazoleN-2 interacts indirectly with Ser319 via a water molecule, with themethyl groups occupying hydrophobic regions of the pocket (Figure 4B). The improved enzyme affinity is likely a resultof the strong pyrazole–water hydrogen bond combined with fitcomplementarity within the binding site. In addition, the compoundmakes all the interactions observed with previous members of the series,including the salt bridge interaction with Leu410/Tyr107, a sandwichedoxadiazole linker, and deeply buried benzothiophene scaffold (Figure 4A).


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 34c (gold) bound to PvNMT.(A) 34c (gold) bound to PvNMT (green), showing piperidine–Leu410salt bridge interaction, deeply buried benzothiophene scaffold, and1,3,5-trimethylpyrazole heterocycle bound within the Ser319 hydrophobicpocket. (B) Enlarged view of the 1,3,5-trimethylpyrazole of 34c (gold) with PvNMT (green). This shows the water-bridgedinteraction between the pyrazole and Ser319, as well as multiple hydrophobiccontacts between the heterocycle and the binding pocket.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Binding mode of 34c (gold) bound to PvNMT.(A) 34c (gold) bound to PvNMT (green), showing piperidine–Leu410salt bridge interaction, deeply buried benzothiophene scaffold, and1,3,5-trimethylpyrazole heterocycle bound within the Ser319 hydrophobicpocket. (B) Enlarged view of the 1,3,5-trimethylpyrazole of 34c (gold) with PvNMT (green). This shows the water-bridgedinteraction between the pyrazole and Ser319, as well as multiple hydrophobiccontacts between the heterocycle and the binding pocket.
Mentions: The binding mode of 34c was elucidatedby crystallography, as briefly described previously20 (Figure 4, PDB entry 2YNE). As predicted during the compound design process, the pyrazoleof 34c does not directly interact with the target Ser319,indicating a subtler basis for the affinity improvement. The pyrazoleN-2 interacts indirectly with Ser319 via a water molecule, with themethyl groups occupying hydrophobic regions of the pocket (Figure 4B). The improved enzyme affinity is likely a resultof the strong pyrazole–water hydrogen bond combined with fitcomplementarity within the binding site. In addition, the compoundmakes all the interactions observed with previous members of the series,including the salt bridge interaction with Leu410/Tyr107, a sandwichedoxadiazole linker, and deeply buried benzothiophene scaffold (Figure 4A).

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