Plerixafor and related macrocyclic amines are potential drug candidates in treatment of malaria by “filling the flap” region of plasmepsin enzymes

• Published in: Medical hypotheses 2018-09, Vol.118, p.68-73
• Main Author: Abiri, Ardavan
• Format: Article
• Language: English
• Subjects: Amines - pharmacology; Antimalarials - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Drug Discovery; Hematopoietic Stem Cells - cytology; Heme; Heme - chemistry; Hemoglobin; Hemoglobins - chemistry; Heterocyclic Compounds - pharmacology; Humans; Macrocycle; Malaria; Malaria - drug therapy; Models, Theoretical; Plasmepsin; Plasmodium falciparum; Plerixafor; Protease Inhibitors - pharmacology; Protein Domains; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Software
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2018.06.020

Death by Plasmodium falsiparum, the leading cause of malaria, is going to remain a major obstacle among the infectious diseases. Plasmepsin aspartic proteases are key proteins in the pathogenesis of plasmodium species which break down the hemoglobin and exploit it as a source of amino acids. These enzymes are one of the favorite targeting agents for medicinal chemists to design new drugs. Plasmepsin proteins show a “flap” region in their N-terminal domain, predisposing them to a good “filler” drug with an exceptional affinity to this enzyme. Plerixafor (Mozobil®, AMD3100), a CXCR4 antagonist with a bicyclam ring, historically discovered as an impurity in a mixture which had anti-HIV properties, is now a FDA approved drug for mobilizing haematopoietic stem cells in cancer patients. In this hypothesis, we focused on the similarity of the structure of plerixafor and its analogues with heme functional group of hemoglobin, the main substrate of plasmepsin, and also with some other recent azamacrocyclic compounds demonstrating antimalarial activity, to test whether these compounds are capable of exhibiting antimalarial activity by inhibiting plasmepsin or not. A preliminary in silico docking study was used to evaluate this hypothesis and docking results indicated that macrocyclic cyclams and cyclens can reliably act as potent lead drug or central pharmacophore in developing new plasmepsin inhibitors as compared with previously designed plasmepsin II inhibitors.