The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study

Abstract

With the aid of density functional calculations, it was revealed that neuraminidase (NA) inhibitors (Scheme 1) exist exclusively in the neutral form. However, the docking and molecular dynamics simulations indicated that the zwitterionic, rather than neutral, isomers are the active form in NA-receptors. The neutral and zwitterionic isomers of BA (Compound 7 in Scheme 1) are quite different in structure and is therefore expected to show distinct bioactivities. With the addition of four water molecules, the geometry of the neutral isomer (nBA4) is induced to resemble the zwitterion and remains rather stable throughout the proton transfer process (nBA4 --> zBA4); in addition, the energy difference between the zwitterionic vs. the neutral isomer is lowered from 24.76 to 2.54 kcal mol(-1). The zwitterion is the predominant isomer in aqueous solution, consistent with the conformational preference in NA-receptors. The proton transfer process of nBA4 --> zBA4 is divided into two elementary steps. Step 1, rather than step 2, plays a decisive role, owing to the larger energy barrier; however, step 1 is not assisted by solvent water, even if it is not water-suppressed. Accordingly, the proton transfer process that leads to the formation of zwitterions is not facilitated in aqueous solution, albeit they may be more stable than the neutral isomers. It is thus suggested that the designed antiviral inhibitors should be facile to transform into the zwitterionic form in aqueous solution. In this way, the oral bioavailability of the antiviral drugs can be improved.

Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors

“…As the backbone-atom root-mean-square deviations (RMSD) in Figure 1 indicate, all the tripeptide-NA complexes that have been energy-minimized remain stable throughout the 1.0 ns MD simulations, consistent with the previous MD results of other NA inhibitors [37–41]. Accordingly, the geometric and energetic analyses are made on the average structures of 500∼1000 ps MD trajectories, where the docked complexes are already at equilibrium.…”

“…On basis of the structures of known anti-influenza virus drugs such as oseltamivir carboxylate and BA [2,14,37,38] and the electrostatic, steric and lipophilic characteristics of NA active sites [1,2,13,23,37,38,42,43], tripeptide FRG was first designed as NA inhibitor. That is, the simplest amino acid Gly is at its C -terminus, which is expected to orient towards the Arg triad (Arg118, Arg292 and Arg371).…”

“…There are reports that tripeptides contribute a lot to clinical research, such as thrombin [33], HIV protease [34], HCV protease [35] and immune systems [36]. On the basis of the evaluations of oseltamivir carboxylate (the active form of oseltamivir) and 4-( N -acetylamino)-5-guanidino-3-(3-pentyloxy) benzoic acid (BA) and three-dimensional information about the NA active site [2,14,37,38], tripeptides FRG, FRV, FHV, YRV, FRT, FRS and FRI were designed as NA inhibitors (Figure S1). The seven tripeptides, optimized with density functional methods, were docked into the NA active site, respectively, and their interaction mechanisms were then studied by explicitly solvated molecular dynamics (MD) simulations.…”

Genome-Wide Identification and in Silico Analysis of Poplar Peptide Deformylases

“…Geometry and partial atomic charges of the tripeptide Met-Ala-Ser were conducted throughout the Discover 3.0 module by applying the BFGS algorithm [31] with a convergence criterion of 0.01 kcal·mol −1 ·Å −1 . As demonstrated by previous results [32,33], the docking simulations were performed to explore and understand the interactions of PtrPDF1A and PtrPDF1B with the tripeptide Met-Ala-Ser using the general protocols in the InsightII 2005 software packages [32,34]. The interaction energies of the substrate with proteins were calculated by the Docking module [34].…”

“…The interaction energies of the substrate with proteins were calculated by the Docking module [34]. More details describing the calculation processes can be found elsewhere [32,33]. …”