Structure-based design of potent and selective leishmania N-myristoyltransferase inhibitors

TY - JOUR

T1 - Structure-based design of potent and selective leishmania N-myristoyltransferase inhibitors

AU - Hutton, Jennie A

AU - Goncalves, Victor

AU - Brannigan, James A

AU - Paape, Daniel

AU - Wright, Megan H

AU - Waugh, Thomas M

AU - Roberts, Shirley M

AU - Bell, Andrew S

AU - Wilkinson, Anthony J

AU - Smith, Deborah F

AU - Leatherbarrow, Robin J

AU - Tate, Edward W

PY - 2014/9/19

Y1 - 2014/9/19

N2 - Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme.

AB - Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme.

U2 - 10.1021/jm5011397

DO - 10.1021/jm5011397

M3 - Article

C2 - 25238611

SN - 0022-2623

VL - 57

SP - 8664

EP - 8670

JO - JOURNAL OF MEDICINAL CHEMISTRY

JF - JOURNAL OF MEDICINAL CHEMISTRY

IS - 20

ER -