Molecular modelling of malaria calmodulin suggests that it is not a suitable target for novel antimalarials.
The recent cloning and sequencing of many calmodulin genes permits alignment of DNA and protein sequences, as well as structural comparison based on homology modelling. The crystal structure of calmodulin places the four Ca(2+)-binding domains in a dumbbell-like configuration, with a large hydrophobic cleft in each half of the molecule. Calmodulin from Plasmodium falciparum has a high level of sequence identity (89%) with its mammalian counterpart. However, a lower degree of sequence conservation is observed among calmodulins from other lower eukaryotes. Potentially important differences in calmodulin sequences involve amino acids with side-chains forming the hydrophobic clefts as well as in the central helix; these differences could alter interactions with small hydrophobic molecules such as chloroquine and with enzymes modulated by calmodulin. Our modelling studies suggest that neither of the antimalarials examined (chloroquine and quinine) bind tightly to calmodulin. We conclude that the differences between host and parasite calmodulins are insufficient to merit this protein being chosen as a realistic target for antimalarial drug design. By contrast, our sequence comparisons reveal that the fungal calmodulins are significantly divergent from those of higher eukaryotes suggesting that at least in these species, calmodulin might be a target for novel antimycotic drugs.
Robson
K J
KJ
MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Headington, U.K.
Gamble
Y
Y
Acharya
K R
KR
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005075:Biological Evolution; D002147:Calmodulin / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D006801:Humans; D008322:Mammals / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
D000962:Antimalarials; D002147:Calmodulin