Insight into the structural similarity between HIV protease and secreted aspartic protease-2 and binding mode analysis of HIV-Candida albicans inhibitors.
The analysis of the structural similarity between Candida albicans Sap2 and HIV-1 aspartic proteases by molecular modeling gave insight into the common requirements for inhibition of both targets. Structure superimposition of Sap2 and HIV-1 protease confirmed the similarity between their active sites and flap regions. HIV-1 protease inhibitors herein investigated can fit the active site of Sap2, adopting very similar ligand-backbone conformations. In particular, key anchoring sites consisting of Gly85 in Sap2 and Ile50 in HIV-1 protease, both belonging to their corresponding flap regions, were found as elements of a similar binding-mode interaction. The knowledge of the molecular basis for binding to both Sap2 and HIV-1 proteases may ultimately lead to the development of single inhibitor acting on both targets.
Department of Chemistry "Ugo Schiff", University of Florence , Florence , Italy.
Chiara
C
Calugi
Antonio
A
Guarna
Andrea
A
Trabocchi
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002176:Candida albicans / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006678:HIV / Q000201:enzymology*; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D005656:Fungal Proteins; D017320:HIV Protease Inhibitors; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C090753:SAP2 protein, Candida