Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors

Abstract

In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC(50) values ranging from 0.5 up to 0.75 µM against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC(50)(0.5 µM), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC(50) values (0.5-10 µM). The PCU-peptides and peptoides were several orders less toxic (145 μM for 11 and 102 μM for 11 peptoid) to human MT-4 cells than lopinavir (0.025 μM). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases. [Figure: see text].

The Impact of Active Site Mutations of South African HIV PR on Drug Resistance: Insight from Molecular Dynamics Simulations, Binding Free Energy and Per‐Residue Footprints

“…As the X‐ray crystal structure of C‐SA HIV PR was not yet resolved, we previously reported the use of a computationally generated enzyme model. The modeling scenario and validation of the created C‐SA HIV PR model have been reported in our previous work . Even though the X‐ray crystal structure of the C‐SA HIV PR (PDB code: 3U71) was recently published , we believe that the use of the modeled enzyme system would still be more appropriate for several reasons.…”

Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

“…The Leap module of amber12 package was used to add missing protons to the protein. Particularly, the protonation state of the catalytic Asp25 residue has been examined in our previous work and other studies, according to our previous investigations, showed that there is no significant difference between the binding free energy results for the monoprotonated and unprotonated states; therefore, the Asp25 residues in this study were left in the unprotonated state . The Amber force field for bioorganic systems (ff03.r1) was used in describing the parameters of the protein, while the inhibitors were described by GAFF parameters as implemented on amber12 .…”

“…Even though this subtype comprises 70% of the global HIV infection to date, very little experimental and computational work on the C‐SA protease has been reported. Publications investigating the impact of active site mutations on binding energies in the C‐SA protease and the inhibition thereof by pentacycloundecane lactam peptides and peptoids make up a substantial proportion of literature on C‐SA protease.…”

“…Ribbon representation of overlay of modelled I36T↑T protease (brown) and wild‐type HIV‐1 subtype C (blue) previously reported (). The amino acid mutations (green), the amino acid insertion (red) and the catalytic Asp (yellow) are highlighted as spheres.…”

A Hybrid Structure/Pharmacophore‐Based Virtual Screening Approach to Design Potential Leads: A Computer‐Aided Design of South African HIV‐1 Subtype C Protease Inhibitors

“…Until late 2012, the X‐ray crystal structure of the C‐SA PR was unavailable, limiting information on how drugs interact with this enzyme. A computational model for the C‐SA PR based on its protein sequence was developed [Mosebi et al., ] and used in previous studies [Makatini et al., 2011a, b, ; Honarparvar et al., ; Karpoormath et al., ]. Recently, the first X‐ray crystal structure of C‐SA HIV PR was reported [Naicker et al., ], allowing comparison of the unique structural and dynamic features of the C‐SA PR enzyme with subtype B.…”