Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)

A Critical Prospect of Structural Designing of Avian Influenza A/H5N1 Neuraminidase Inhibitors That Evade Tamiflu Resistance

“…It was demonstrated that the 150-cavity can be exploited for designing novel inhibitors of H5N1 NA [3,9] in the same way as experimentally proposed [5]. The relevance of these observations [3,[7][8][9] was questioned by pointing out both that an improper initial structure (PDB ID: 2HU0) was used and that a "closed" conformation of the N1:OTV cocrystal structure is more appropriate for such studies [10]. Even though the discrepancies between the theoretical [7] and experimental [11] structures of the His274Tyr N1:OTV protein:ligand complexes were initially observed, the inclusion of protein flexibility, especially in the region of 150-loop, in the molecular docking protocol successfully fixed the glitch [12,13].…”

“…The "open" conformation of the crystal structure of H5N1 NA in complex with OTV (PDB ID: 2HU0) was used to rationalize the molecular mechanism of oseltamivir resistance using molecular docking simulations [3,7,8]. It was demonstrated that the 150-cavity can be exploited for designing novel inhibitors of H5N1 NA [3,9] in the same way as experimentally proposed [5].…”

Design Of Novel Anti-Influenza Drugs That Circumvent Oseltamivir Resistance: A Critical Perspective

“…The relevance of these observations [4][5][6][7] was questioned by pointing out both that an improper initial structure (PDB ID: 2HU0) was used and that a 'closed' conformation of the N1:OTV co-crystal structure is more appropriate for such studies [8]. Even though the discrepancies between the theoretical [5] and experimental [9] structures of the His274Tyr NA:OTV protein:ligand complexes were initially observed, the inclusion of protein flexibility, especially in the region of 150-loop, in the molecular docking protocol successfully fixed the glitch *Corresponding author: Dr. Petar M Mitrasinovic, Belgrade Institute of Science and Technology, 11060 Belgrade, Serbia, E-mail: petar.mitrasinovic@yahoo.com [10,11]. This quite a remarkable rationalization was in agreement with the previously proven considerable flexibility of the residues in the 150-loop of N1 from avian H5N1 [12].…”

“…The 'open' conformation of the crystal structure of H5N1 NA in complex with OTV (PDB ID: 2HU0) was used to rationalize the molecular mechanism of oseltamivir resistance using molecular docking simulations [4][5][6]. It was demonstrated that the 150-cavity can be exploited for designing the more potent inhibitors of H5N1 NA [4,7] in the same way as experimentally proposed [2].…”

“…Moreover, the possibility of designing more potent OTV derivatives than OTV itself was illustrated by both employing the 'open' conformation of the NA crystal structure (PDB ID: 2HU0) and taking advantage of the presence of the 150-cavity nearby the N1 NA active site [13]. It was concluded that the 'open' form crystal structure of 2HU0 provides a novel and reliable structural basis for rational drug design against influenza virus [13], thus speaking in favor of all the previous studies [4][5][6][7] being based upon the experimental proposal of Russell et al [2]. This conclusion was substantiated by molecular dynamics simulations [12,14] focusing on the functional behavior of 150-loop in N1 from avian H5N1.…”