Molecular Docking, Synthesis and anti-HIV-1 Protease Activity of Novel Chalcones

Abstract

Background: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. Objective: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. Methods: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. Results: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 μM, which is comparable with commercial product Darunavir. Conclusion: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.

Isolation and Characterization of Two Chalcone Derivatives with Anti-Hepatitis B Virus Activity from the Endemic Socotraen Dracaena cinnabari (Dragon’s Blood Tree)

“…Their intriguing biological properties have been investigated as potential pharmacological compounds having the ability to target a wide range of human viruses, such as hepatitis B virus (HBV), hepatitis C virus, MERS-CoV, SARS-CoV, human rhinovirus, herpes simplex, HIV, and influenza virus. Many viral molecular targets have been demonstrated to be affected by chalcones, including reverse transcriptase, protease, neuraminidase, aminotransferases, peroxide dismutase, glutathione peroxidase, and other related enzymes [27][28][29][30].…”

A comprehensive review on the antiviral activities of chalcones

“…Figure 1 illustrates the main mechanisms of actions of chalcone derivatives that were reported in literature on different human viruses. Chalcones were shown to act on important viral molecular targets affecting different stages of viral replication cycle including; reverse transcriptase (RT) [31,32], IN [22,[33][34][35], protease [36][37][38], neuraminidase (NA) [39], aminotransferases [40], superoxide dismutase, glutathione peroxidase and other associated enzymes [40]. They were also found to act on important receptors such as CXCR4 chemokine receptors [41], US28 receptor of HCMV [27] and capsid pocket inside viral protein 1 (VP1) in rhinovirus [42].…”

“…The vast majority of them were explored on HIV infection (with major focus on HIV-1 subtype). As summarised in Table 1, the main HIV targets that were investigated with chalcone were RT [31,32], IN [22,[33][34][35] and protease [36][37][38] enzymes. Some chalcones were investigated for their inhibitory potential on viral replication without specifying their exact targets [49,51].…”

“…Among them, a derivative based on the chalcone pharmacophore had potently inhibited the IN mediated 3 0 processing (IC 50 : 1.9 lM) and strand transfer (ST) processes (IC 50 : 0.6 lM) [34]. Protease enzyme is another target that was studied for chalcone anti-HIV actions [36][37][38]. Turkovic et al reported the discovery of a very active chalcone derivative exhibiting a potent inhibitory activity towards protease enzyme (IC 50 value of 0.001 lM) [36].…”

“…Protease enzyme is another target that was studied for chalcone anti-HIV actions [36][37][38]. Turkovic et al reported the discovery of a very active chalcone derivative exhibiting a potent inhibitory activity towards protease enzyme (IC 50 value of 0.001 lM) [36].…”