Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design.
Myristoyl-CoA:protein N-myristoyltransferase (NMT) is a cytosolic monomeric enzyme that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the N-terminal glycine of a number of eukaryotic cellular and viral proteins. Recent experimental data suggest NMT from parasites could be a promising new target for the design of novel antiparasitic agents with new mode of action. However, the active site topology and inhibitor specificity of these enzymes remain unclear. In this study, three-dimensional models of NMT from Plasmodium falciparum (PfNMT), Leishmania major (LmNMT) and Trypanosoma brucei (TbNMT) were constructed on the basis of the crystal structures of fungal NMTs using homology modeling method. The models were further refined by energy minimization and molecular dynamics simulations. The active sites of PfNMT, LmNMT and TbNMT were characterized by multiple copy simultaneous search (MCSS). MCSS functional maps reveal that PfNMT, LmNMT and TbNMT share a similar active site topology, which is defined by two hydrophobic pockets, a hydrogen-bonding (HB) pocket, a negatively-charged HB pocket and a positively-charged HB pocket. Flexible docking approaches were then employed to dock known inhibitors into the active site of PfNMT. The binding mode, structure-activity relationships and selectivity of inhibitors were investigated in detail. From the results of molecular modeling, the active site architecture and certain key residues responsible for inhibitor binding were identified, which provided insights for the design of novel inhibitors of parasitic NMTs.
Sheng
Chunquan
C
School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, Shanghai, People's Republic of China.
Ji
Haitao
H
Miao
Zhenyuan
Z
Che
Xiaoyin
X
Yao
Jianzhong
J
Wang
Wenya
W
Dong
Guoqiang
G
Guo
Wei
W
Lü
Jiaguo
J
Zhang
Wannian
W
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D056890:Eukaryota / Q000201:enzymology*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D018320:Leishmania major / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010271:Parasites / Q000201:enzymology; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014346:Trypanosoma brucei brucei / Q000201:enzymology
D004791:Enzyme Inhibitors; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase