title: Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: a hybrid 2D NMR and docking/QM/MM/MD approach.
abstract: Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.
authors: School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban 4001, South Africa.
authors: Maya M
authors: MM
authors: Makatini
authors: Katja
authors: K
authors: Petzold
authors: Shimoga N
authors: SN
authors: Sriharsha
authors: N
authors: N
authors: Ndlovu
authors: Mahmoud E S
authors: ME
authors: Soliman
authors: Bahareh
authors: B
authors: Honarparvar
authors: Raveen
authors: R
authors: Parboosing
authors: Anneta
authors: A
authors: Naidoo
authors: Per I
authors: PI
authors: Arvidsson
authors: Yasien
authors: Y
authors: Sayed
authors: Patrick
authors: P
authors: Govender
authors: Glenn E M
authors: GE
authors: Maguire
authors: Hendrik G
authors: HG
authors: Kruger
authors: Thavendran
authors: T
authors: Govender
mesh_terms: D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D017320:HIV Protease Inhibitors / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D001952:Bridged-Ring Compounds; D017320:HIV Protease Inhibitors