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  • To date three other allosteric binding

    2021-11-29

    To date, three other allosteric binding sites of HIV-1 IN have also been reported. In the work of Wielens and co-workers [33], a pocket formed by the residues Tyr83, Trp108, Asn184, Ile200 and Val201 was found, which can be bound by small molecules. In the work by Rhodes et al. [34], a small-molecule-interacting pocket formed by His183, Gln62 and Ser147 was found. In other work by Wielens et al.[35], another site was observed, formed by residues Asp64, Asp116, Asn144, Gln146, Gln148 and Glu153, where a sucrose molecule binds. Figure 4 indicates the 3D structure of the protein related to the three binding sites mentioned above. Figure 4b was generated by superimposing the co-crystal structure of IN–BAX (PDB code: 3AO1) [33], the co-crystal structure of IN–IWV (PDB code: 3NF6) [34] and the co-crystal structure of IN–sucrose (PDB code: 3L3V) [35]. It is possible for us to design new potential inhibitors for binding IN at these binding sites for AIDS therapy.
    HIV-1 INSTIs Molecules inhibiting the 3′P step, the ST step or the interactions between LEDGF/p75 and IN could show inhibitory effects on HIV-1 IN. Some HIV-1 IN inhibitors were reviewed 2, 48, 49, 50, including natural product inhibitors, peptide inhibitors and synthetic small molecule inhibitors. The structures of the natural products and peptides were complicated, and their inhibitory effects on HIV-1 IN were moderate or weak. By contrast, some small molecule inhibitors presented a satisfactory inhibitory effect on HIV-1 IN. Therefore, researchers focused on the small molecule inhibitors, and a vast amount of data on the inhibitory activities of them is available today. Much work on the HIV-1 INSTIs has been done. Three HIV-1 INSTI drugs: raltegravir (RAL) [51], elvitegravir (EVG) [52] and dolutegravir (DTG) [53] have been approved by FDA. Their structures are shown in Fig. 5. We have classified hundreds of HIV-1 INSTIs into active (IC50<100μm) and weakly active (IC50>100μm), and the inhibitors were also classified into ten classes according to their scaffolds (Table 2) [40]. To study which scaffolds contribute to the high activity of HIV-1 INSTIs, 817 compounds were collected from the ten classes, and a cluster analysis was performed using Kohonen's self-organizing map (SOM) [54]. Scaffold 1 (class I) has a core of β-diketo Nitrotetrazolium Blue chloride or its derivatives. One-hundred-and-six inhibitors contained scaffold 1, including 95 active and 11 weakly active inhibitors. Scaffold 2 (class II) involves a core of naphthyridinecarboxamides, quinolones or compounds isosteric to them. Class II was made up of 183 active and 32 weakly active inhibitors. Scaffold 3 (class III) has a core scaffold of pyrimidinones, and 114 active and four weakly active inhibitors contained scaffold 3. Class IV was made up of five active and 16 weakly active inhibitors containing thiazolothiazepine (scaffold 4). Scaffold 5 (class V) involves styrylquinolines, chicoric acid, caffeic acid phenethyl ester and some other compounds that have multi-hydroxy groups, and class V contained 46 active and 32 weakly active inhibitors. Scaffold 6 (class VI) has a core of disulfones, and eight active and 12 weakly active inhibitors were contained in this class. Scaffold 7 (class VII) contains benzsulfamide, and this class contained 45 active and 31 weakly active inhibitors. Class VIII contained 22 active and 15 weakly active inhibitors with a core coumarin ring (scaffold 8). Scaffold 9 (class IX) has a core of salicylhydrazine, and the amount of the active and weakly active inhibitors with this scaffold was 14 and 29, respectively. The remaining inhibitors were grouped as class X, which contained 64 active and 39 weakly active inhibitors (the structures of inhibitors in class X were diverse; therefore we could not summarize a scaffold). The structures of scaffolds and some representative molecules are shown in Table 2.
    Essential features of HIV-1 INSTIs From above, it can be observed that most compounds in classes I–III containing the scaffolds 1–3 (β-diketo acid, naphthyridinecarboxamide or pyrimidinones) were active inhibitors. Earlier in this article (Fig. 2b), we summarized that the typical interactions between these three classes of inhibitors and HIV-1 IN and the common interaction for them was chelation with Mg2+ ions. This might indicate that chelation was one of the most important factors that affected the inhibitory activity of candidate, and scaffolds like β-diketo acid and its derivatives, naphthyridinecarboxamide (or the isosteres of it) and pyrimidinones can have a crucial role in the activity of HIV-1 INSTIs. After comparing the molecular structures of active inhibitors with those of weakly active inhibitors, it can be found that a lot of inhibitors of classes I–III contain a halogenated benzyl group (fluorine or chlorine), which is a common structural feature. In the work by Hare et al.[103], the authors explain the mechanism where the halogen atom caused an outward shift of the phenyl ring and altered the contact with the base of the viral DNA. From these ten classes of compounds it can also be observed that, for most HIV-1 INSTIs, a hydrogen donor and a hydrogen acceptor separated by two or three intervening atoms is essential, because such a substructure is responsible for the binding of a metal ion.