Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase

Abstract

Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches.Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors.

In search of therapeutic candidates for HIV/AIDS: rational approaches, design strategies, structure–activity relationship and mechanistic insights

“…Lavendustin-B 180 is a natural product that has been identied as an allosteric inhibition inducer of the HIV-1 integrase enzyme. 123 Integration is an important step for HIV replication, through which the viral genome gets inserted into the host genome for transcription of new viral proteins. [124][125][126][127][128][129][130][131][132][133] Several other allosteric integrase inhibitors have been evolved, which act on the LEDGF/p75 binding site and inhibit the process of integration.…”

“…In the last step, the desired lavendustin B derivatives 181-183, 185, 186, and 188 were formed by treating compounds 200-205 with sodium hydroxide and methanol. 123 The anti-HIV potential of all the lavendustin B derivatives was evaluated for their inhibitory activity against IN-LEDGF/p75 binding using HTRF mM and 3.28 mM against IN-LEDGF/p75 binding, respectively. The most potent compound 182 together with its docking features are also presented in Fig.…”

“…21. 123 2.12. 3,7-Dihydroxytropolone-based analogs 3,7-Dihydroxytropolones are oxygenated troponoid compounds, which have been used as potential agents against several human disorders including viral infections.…”

Extracting functional groups of ALLINI to design derivatives of FDA‐approved drugs: Inhibition of HIV‐1 integrase

“…EVG, RAL, and DTG share a common mechanism of action, in which they bind at the HIV‐1 IN active site in the presence of the viral DNA and inhibit the strand transfer activity. Though these three FDA‐approved inhibitors have been highly active against HIV, resistant mutations have appeared in patients . Thus, there is a continuous need for developing new HIV‐1 IN inhibitors that can target alternative sites of the enzyme to overcome the resistance problem.…”

“…Recent studies have led to the development of a new group of allosteric integrase inhibitors (ALLINIs). And the structure of ALLINIs bound at the CCD–CCD dimer aided the rapid extension of this class of inhibitors. Several studies have shown that ALLINIs inhibit multiple functions of wild‐type integrase, and these compounds occupy a binding pocket at the integrase dimer interface .…”