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Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors : A hybrid 2D NMR and docking/QM/MM/MD approach

Makatini, Maya M. (author)
Petzold, Katja (author)
School of Chemistry, University of KwaZulu-Natal, Varsity Drive, Durban 4001, South Africa
Sriharsha, Shimoga N. (author)
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Ndlovu, N. (author)
Soliman, Mahmoud E. S. (author)
Honarparvar, Bahareh (author)
Parboosing, Raveen (author)
Naidoo, Anneta (author)
Arvidsson, Per I. (author)
Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
Sayed, Yasien (author)
Govender, Patrick (author)
Maguire, Glenn E. M. (author)
Kruger, Hendrik G. (author)
Govender, Thavendran (author)
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 (creator_code:org_t)
Elsevier BV, 2011
2011
English.
In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 46:9, s. 3976-3985
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Keyword

Pentacycloundecane (PCU) peptides
HIV protease inhibitor
EASY-ROESY
Docking
QM/MM/MD
Molecular dynamics simulation

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