2020同步年報

Life Science 053 PDE5 catalytic domain, one avanafil, one Zn 2+ , one Mg 2+ and one sulfate ( Fig. 1(a) ). A distinct feature of avanafil is the employment of a halogen-substituted benzyl moiety, the 3-chloro-4-methoxybenzene ring, to mediate target bind- ing ( Fig. 1(b) ). The interactions between PDE5 and avanafil are mainly through noncovalent interactions of multiple types and a unique, avanafil-specific, halogen bond ( Fig. 1(c) ). The hydrogen bonds are shown as green dashed lines, and residues making van der Waals interactions with avanafil are shown in red arcs with spokes. A779, of which the carbonyl oxygen forms a halogen bond with avanafil, is shown as a green arc with spokes. A water molecule (cyan) bridges the interaction between avanafil and α16. The chlo- rine atom of this aryl halide moiety is located atypically near (3.0 Å) the carbonyl oxygen of A779 ( Fig. 1(d) ), indicating the formation of a halogen bond between Cl and O. A key feature of this halogen bond formed between avanafil and PDE5 is that A779, the halogen-bond acceptor, belongs to helix α14 ( Fig. 1(d) ). This finding illustrates that particular main-chain carbonyl-oxygen atoms from α-helices can participate in protein−ligand interactions through acting as a halogen-bond acceptor. Furthermore, this chlorine atom makes van der Waals interactions with side chains of nearby residues (A779, V782 and A783) that form a binding pocket ( Fig. 1(e) ). This finding demonstrates that the accessibility of such a carbonyl oxygen depends on the width of the hole entrance that is determined by the sizes and shapes of the surrounding side chains. In summary, the crystal structure of the PDE5−avanafil complex was determined at resolution 1.9 A. Analysis of the protein−drug interactions reveals the structure−activity relation of avanafil and provides a molecular basis of its superior isoform selectivity. Moreover, a halogen bond was observed between the aryl halide moiety of avanafil and a backbone carbonyl oxygen from an α-helix flanking the drug-binding site, which illustrates the feasibility of exploit- ing the α-helix backbone in structure-based drug develop- ment. (Reported by Chia-Liang Lin) This report features the work of Nei-Li Chan and his col- leagues published in J. Med. Chem. 63 , 8485 (2020). TLS 15A1 Biopharmaceuticals Protein Crystallography TLS 13C1 SW60 – Protein Crystallography • Protein Crystallography • Biological Macromolecules, Protein Structures, Life Science References 1. M. Packer, J. R. Carver, R. J. Rodeheffer, R. J. Ivanhoe, R. Dibianco, S. M. Zeldis, G. H. Hendrix, W. J. Bommer, U. Elkayam, M. L. Kukin, G. I. Mallis, J. A. Sollano, J. Shannon, P. K. Tandon, D. L. Demets, N. Engl. J. Med. 325 , 1468 (1991). 2. L. M. Fabbri, P. M. Calverley, J. L. Izquierdo-Alonso, D. S. Bundschuh, M. Brose, F. J. Martinez, K. F. Rabe, Lancet 374 , 695 (2009). 3. A. Morales, C. Gingell, M. Collins, P. A. Wicker, I. H. Osterloh, Int. J. Impotence Res. 10 , 69 (1998). 4. W. J. Hellstrom, M. Gittelman, G. Karlin, T. Segerson, M. Thibonnier, T. Taylor, H. Padma-Nathan, J. Androl. 23 , 763 (2002). 5. H. Padma-Nathan, J. G. McMurray, W. E. Pullman, J. S. Whitaker, J. B. Saoud, K. M. Ferguson, R. C. Rosen, Int. J. Impotence Res. 13 , 2 (2001). 6. T. Sakamoto, Y. Koga, M. Hikota, K. Matsuki, M. Murakami, K. Kikkawa, K. Fujishige, J. Kotera, K. Omori, H. Morimoto, K. Yamada, Bioorg. Med. Chem. Lett. 24 , 5460 (2014). 7. C.-M. Hsieh, C.-Y. Chen, J.-W. Chern, N.-L. Chan, J. Med. Chem. 63 , 8485 (2020).