Limits...
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.

Show MeSH

Related in: MedlinePlus

X-ray crystal structure of 20b (blue) boundto PvNMT (green). (A) 20b bound to PvNMT. The 3-methoxyphenylsubstituent forms the intended interactions with Ser319 and Phe105,in addition to the deeply buried hydrophobic scaffold and salt bridgeinteraction observed in 1. (B) The oxadiazole linkeris sandwiched between two aromatic residues, rationalizing the affinityenhancement in moving to an aromatic heterocycle from the ester linkerin 4b. Dashed lines are drawn to highlight key interactionsbetween the enzyme and the ligand.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4048319&req=5

fig2: X-ray crystal structure of 20b (blue) boundto PvNMT (green). (A) 20b bound to PvNMT. The 3-methoxyphenylsubstituent forms the intended interactions with Ser319 and Phe105,in addition to the deeply buried hydrophobic scaffold and salt bridgeinteraction observed in 1. (B) The oxadiazole linkeris sandwiched between two aromatic residues, rationalizing the affinityenhancement in moving to an aromatic heterocycle from the ester linkerin 4b. Dashed lines are drawn to highlight key interactionsbetween the enzyme and the ligand.

Mentions: Crystallography confirmed the binding mode of 20b inthe peptide substrate pocket of PvNMT (Figure 2A, PDB entry 4CAE), showing that the methoxyphenyl moiety makes hydrophobic contactswith Phe105 and a polar contact with Ser319, in addition to the interactionsobserved previously for 1.21 Furthermore, the oxadiazole is “sandwiched” betweenthe aromatic residues Phe105 and Tyr211, potentially explaining theaffinity improvement observed when the ester in 4b isreplaced by an oxadiazole in 9c/14b (Figure 2B).


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-ray crystal structure of 20b (blue) boundto PvNMT (green). (A) 20b bound to PvNMT. The 3-methoxyphenylsubstituent forms the intended interactions with Ser319 and Phe105,in addition to the deeply buried hydrophobic scaffold and salt bridgeinteraction observed in 1. (B) The oxadiazole linkeris sandwiched between two aromatic residues, rationalizing the affinityenhancement in moving to an aromatic heterocycle from the ester linkerin 4b. Dashed lines are drawn to highlight key interactionsbetween the enzyme and the ligand.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: X-ray crystal structure of 20b (blue) boundto PvNMT (green). (A) 20b bound to PvNMT. The 3-methoxyphenylsubstituent forms the intended interactions with Ser319 and Phe105,in addition to the deeply buried hydrophobic scaffold and salt bridgeinteraction observed in 1. (B) The oxadiazole linkeris sandwiched between two aromatic residues, rationalizing the affinityenhancement in moving to an aromatic heterocycle from the ester linkerin 4b. Dashed lines are drawn to highlight key interactionsbetween the enzyme and the ligand.
Mentions: Crystallography confirmed the binding mode of 20b inthe peptide substrate pocket of PvNMT (Figure 2A, PDB entry 4CAE), showing that the methoxyphenyl moiety makes hydrophobic contactswith Phe105 and a polar contact with Ser319, in addition to the interactionsobserved previously for 1.21 Furthermore, the oxadiazole is “sandwiched” betweenthe aromatic residues Phe105 and Tyr211, potentially explaining theaffinity improvement observed when the ester in 4b isreplaced by an oxadiazole in 9c/14b (Figure 2B).

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