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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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X-raycrystal structure of 20b (blue) bound to PvNMT (green).Further inspection of the water molecules within the active site showsthat the benzylic CH2 occupies a heavily solvated pocket,indicating that substitution may result in more favorable energeticswithin the enzyme active site. Dashed lines indicate water moleculeswithin 5 Å of the benzylic position.
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fig3: X-raycrystal structure of 20b (blue) bound to PvNMT (green).Further inspection of the water molecules within the active site showsthat the benzylic CH2 occupies a heavily solvated pocket,indicating that substitution may result in more favorable energeticswithin the enzyme active site. Dashed lines indicate water moleculeswithin 5 Å of the benzylic position.

Mentions: The crystal structure of 20b bound to PvNMT indicatedthat there was a voluminous solvent-filled pocket surrounding themethylene group α to the methoxyphenyl, inviting the introductionof functionality that could either stabilize the water molecules inthis pocket or displace water to the bulk solvent (Figure 3).38,39 In addition, this position isa potential target for oxidative metabolism and blocking with alternativesubstituents may provide benefits during subsequent lead development.


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)

X-raycrystal structure of 20b (blue) bound to PvNMT (green).Further inspection of the water molecules within the active site showsthat the benzylic CH2 occupies a heavily solvated pocket,indicating that substitution may result in more favorable energeticswithin the enzyme active site. Dashed lines indicate water moleculeswithin 5 Å of the benzylic position.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: X-raycrystal structure of 20b (blue) bound to PvNMT (green).Further inspection of the water molecules within the active site showsthat the benzylic CH2 occupies a heavily solvated pocket,indicating that substitution may result in more favorable energeticswithin the enzyme active site. Dashed lines indicate water moleculeswithin 5 Å of the benzylic position.
Mentions: The crystal structure of 20b bound to PvNMT indicatedthat there was a voluminous solvent-filled pocket surrounding themethylene group α to the methoxyphenyl, inviting the introductionof functionality that could either stabilize the water molecules inthis pocket or displace water to the bulk solvent (Figure 3).38,39 In addition, this position isa potential target for oxidative metabolism and blocking with alternativesubstituents may provide benefits during subsequent lead development.

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