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  • As evidenced by SARs and crystallographic data

    2021-10-13

    As evidenced by SARs and crystallographic data, HO-1 has at least three main crucial regions for inhibitor binding. The most crucial area, the so-called eastern region, is able to allocate the azole ring that represents the first anchoring point by establishing a coordination binding to the heme ferrous iron. The northeastern and western regions, located in the near and distal area respectively, form two hydrophobic pockets able to stabilize the inhibitor binding further and account for potency and selectivity. The western region extends back into the distal side of the heme-binding pocket constituting another small hydrophobic pocket able to allocate moieties of variable sizes (e.g., aryl, heteroaryl, etc.) [26,37]. The correct vadadustat sale of compound 7 (Fig. 2) in the primary and secondary pockets of the western region has highlighted the importance of the western region of the enzyme. A double-clamp ligand seems to be a good strategy to improve the potency of inhibitors [38]. Drug design studies have reported some crucial aspects that need to be considered to achieve optimal levels of potency and selectivity for HO-1/HO-2 inhibitors. Salerno et al. have reported the design, synthesis, and molecular modeling of new potent and selective imidazole HO-1 inhibitors (Table 5, compounds 13a–g) availing from the following considerations: i) the volume of the main cavity near the heme group of the HO-2 isoform (PDB ID 2QPP) is larger than 34 Å3 compared to the HO-1 isoform (PDB ID 1N45); ii) the analog analyses conducted on five known corresponding HO-1/ligand co-crystallized forms (PDB ID 2DY5, 3CZY, 3K4F, 3HOK, and 3TGM) showed that the flexibility of the binding cavity allows an adaptation of the ligands as the cavities can increase and adapt to the ligand in the closed structure; iii) the molecules with higher power and selectivity for HO-1 have an averaged Van der Waals volume of 274.34 Å3, with a range of 239.00–302.87 Å3; iv) the most potent and selective HO-2 inhibitors have an average Van der Waals volume of 284.10 Å3 with a range of 274.37–306.75 Å3 [62]. The docking studies showed that the newly synthesized imidazole-based inhibitors present the nitrogen atom of the imidazole ring correctly anchored to the ferrous iron of the heme group. In the docked structures, the substituted phenylethanolic linker of the newly designed inhibitors is always located in the western region of the binding pocket, whereas the northeastern pocket remains free. Compound 13a (Table 5) turns out to be the most potent inhibitor of the series, with a SI 80 towards HO-2. The phenyl group interactions in the main pocket of the western region were with Leu54, Phe167, Val50, and Arg136, while bromine points towards the outer portion of the binding pocket. The most selective compound towards HO-2, 13b (SI HO-2/HO-1 >111), shows that the aromatic linker is accommodated inside the western cavity, while the phenyl at the 3-position points outside this cavity. In an attempt to demonstrate the importance of the role of secondary hydrophobic pockets, three new HO-1 inhibitors based on imidazole have been designed and synthesized by Greish et al. [63] (Fig. 4). Molecular modeling studies have proved that the imidazole of compounds 14, 15 (Fig. 4) correctly interacts with the iron of the heme group. On the other hand, the substituted phenylethanolic moiety is always located in the western region of the binding pocket. Compound 13g (Table 5), does not allocate the benzyl group in the secondary binding pocket of the western region of HO-1; differently, the benzyl group is located in the northeastern pocket (Asn210, Ala31, Ile211, Ala28, and Glu32) in a similar pose of the aromatic region (trifluoromethyl pyridine), analog to compound 2 (Fig. 2). It is important to note that the modification of this region of the HO-1 enzyme does not affect power and selectivity; instead, it could negatively influence the power of the inhibitor. In fact, compound 13g is about 200 times less potent than the analogous progenitor. Differently, the bromophenyl moiety of the molecules is appropriately allocated in the wester-principal region (Phe47, Val50, Phe167, Leu147, Leu54 and Arg136) and the bromine is directing to the external portion inside the western region. Compound 15 is well located inside the binding pocket with a similar pose to that of the mother compound 7.