title: Synthesis and molecular modelling studies of novel carbapeptide analogs for inhibition of HIV-1 protease.
abstract: Novel glycopeptides containing amino acids such as valine and alanine were designed, synthesized and tested for inhibition of the wild type C-SA HIV-1 protease enzyme. The incorporation of dipeptide sequences Val-Ala/Ala-Val to the sugar B-amino acid at two side chain positions resulted in a series of nine novel compounds. Compounds 3a, 3b, 3c, 3d, 4a, 4b and 5 displayed significant activities against the HIV protease enzyme. The glycopeptides are orders of magnitude less toxic to human MT-4 cells than lopinavir. Computational results were in good agreement with the experimental HIV-PR activity. The sugar hydroxyl group at the C(3) position interacts with the enzymatic Asp25/Asp25' residues. The docked position of the inhibitor is preserved during MD simulations and at least five hydrogen bond forms between the inhibitor and the enzymatic pocket. The results provide a platform for the progress of more effective carbohydrate supported inhibitors of HIV-1 and other aspartic proteases.
authors.affiliation: School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban, KwaZulu-Natal 4000, South Africa.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Pawar
authors.forename: Amit M
authors.initials: AM
authors.lastname: Jabgunde
authors.forename: Patrick
authors.initials: P
authors.lastname: Govender
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.forename: Raveen
authors.initials: R
authors.lastname: Parboosing
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Dhavale
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
mesh_terms: D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D004952:Esters; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011487:Protein Conformation
chemical_list: D004952:Esters; D006020:Glycopeptides; D011480:Protease Inhibitors; D016333:HIV Protease