Phenanthridine derivatives as potential HIV-1 protease inhibitors

Abstract

In the present study, the antiviral activity of phenanthridine derivatives was assessed. In total, the inhibitory effect of eight structurally similar low-molecular-weight hydrophobic compounds on HIV-1 protease (HIVp) was investigated. HIVp is a key enzyme in the HIV-1 life cycle. Surface plasmon resonance technology was used for affinity assessment of compounds binding with either monomeric or dimeric forms of HIVp. HIVp enzyme inhibition assays with chromogenic substrate VII were also used to determine the IC₅₀ values. The most potent compound was 3,3,9,9-tetramethyl-3,4,9,10-tetrahydro-2H,8H-phenanthridine-1,7-dione which binds to monomeric and dimeric forms of HIVp (apparent dissociation constant, 2-7 µM; IC₅₀, 36 µМ), while possessing the most favorable Absorption, Distribution, Metabolism and Excretion parameters. Molecular docking simulations highlighted certain differences in the binding patterns of the phenanthridine derivatives with HIVp amino acid residues forming the flaps domain, monomer/monomer interfaces and the active site cavity of HIVp. Thus, it was hypothesized that the inhibitory effect of phenanthridine compounds on the enzymatic activity of HIVp may be due to restriction of substrate access to the HIVp active site.

Keywords: HIV1 protease; dimer; enzyme inhibition; monomer; phenanthridine derivatives; surface plasmon resonance.

Figure 1

HIV-1 protease IC₅₀ value calculation for compound 2a.

Figure 2

Flow chart of the experimental procedure used in the present study to identify the potential value of the phenanthridine derivatives as HIV-1 protease inhibitors, and the binding parameters and predicted binding site of compound 2a. SPR, surface plasmon resonance; K_d apparent dissociation constant; ADME, Absorption, Distribution, Metabolism and Excretion.