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. 2024 Sep 19;4(5):242-256.
doi: 10.1021/acsbiomedchemau.4c00040. eCollection 2024 Oct 16.

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors

Muhammad Asad Ur Rehman  1 , Hathaichanok Chuntakaruk  2   3 , Soraat Amphan  2 , Aphinya Suroengrit  4   5 , Kowit Hengphasatporn  6 , Yasuteru Shigeta  6 , Thanyada Rungrotmongkol  2   3 , Kuakarun Krusong  2 , Siwaporn Boonyasuppayakorn  4 , Chanat Aonbangkhen  1 , Tanatorn Khotavivattana  1
Affiliations

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors

Muhammad Asad Ur Rehman et al. ACS Bio Med Chem Au. .

Abstract

Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1' and P2', to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2' substitution was found to be effective, as seen in 5aa (1.54 nM), 5ad (0.71 nM), 5ac (0.31 nM), 5ae (0.28 nM), and 5af (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly 5ae, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2' subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Overview of designs of darunavir analogs previously reported and in the present study.
Figure 2
Figure 2
Structures of the DRV scaffold and different substituting groups for the P1′ and P2′ modifications.
Figure 3
Figure 3
Synthesis of DRV analogs; reagents and conditions: (i) EtOH, 80 °C, 3 h, 60–85%; (ii) TEA, CH2Cl2, 0–25 °C, o/n, 23–83%; (iii) TFA-DCM (1:1), 0–25 °C, o/n, 95–100%; (iv) TEA, CH2Cl2, 25 °C, o/n, 13–50%.
Figure 4
Figure 4
SAR analysis of DRV analog.
Figure 5
Figure 5
3D diagram of ligand–protein interactions for the five selected analogs with WT HIV-1 PR compared to DRV.
Figure 6
Figure 6
(a) All-atom RMSD, # H-bonds, and # Atom contacts of DRV (left) and 5ae (right) in complex with WT HIV-1 PR plotted along the 100 ns MD simulation. (b) Crucial interactions of DRV and 5ae in complex with WT HIV-1 PR are depicted in 2D and 3D pharmacophore models, along with the representative pharmacophore models (RPMs) analyzed from the last 20 ns of MD simulations. Green arrow, red arrow, and yellow circle represent the pharmacophore features of hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), and hydrophobic interaction, respectively.
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