Synthesis of New (−)-Bestatin-Based Inhibitor Libraries Reveals a Novel Binding Mode in the S1 Pocket of the Essential Malaria M1 Metalloaminopeptidase
| Autor: | Michael Klemba, Geetha Velmourougane, Seema Dalal, Doron C. Greenbaum, Nataline Meinhardt, Michael B. Harbut, Sheena McGowan, James C. Whisstock, Christine A Oellig |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Stereochemistry Plasmodium falciparum Plasma protein binding CD13 Antigens Crystallography X-Ray Article Small Molecule Libraries Antimalarials Structure-Activity Relationship chemistry.chemical_compound Leucine Drug Discovery medicine Structure–activity relationship Binding site Binding Sites Dipeptide Natural product Molecular Structure biology Chemistry Stereoisomerism biology.organism_classification medicine.disease Biochemistry Molecular Medicine Malaria Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 54:1655-1666 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm101227t |
| Popis: | The malarial PfA-M1 metallo-aminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-d-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the α-hydroxy-β-amino acid (P1) or the adjacent natural α-amino acid (P1'). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBzl) 16 at the P1 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PfA-M1 pocket that interacts with the P1 side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria. |
| Databáze: | OpenAIRE |
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