Theoretical Studies on the Susceptibility of Oseltamivir against Variants of 2009 A/H1N1 Influenza Neuraminidase

Abstract

The outbreak and high speed global spread of the new strain of influenza A/H1N1 virus in 2009 posed a serious threat to global health. It is more likely that drug-resistant influenza strains will arise after the extensive use of anti-influenza drugs. Consequently, the identification of the potential resistant sites for drugs in advance and the understanding of the corresponding molecular mechanisms that cause drug resistance are quite important in the design of new drug candidates with better potency to combat drug resistance. Here, we performed molecular simulations to evaluate the potency of oseltamivir to combat drug resistance caused by the mutations in 2009 A/H1N1 neuraminidase (NA). We examined three representative drug-resistant mutations in NA, consisting of H274Y, N294S, and Y252H. First, a theoretical structure of A/H1N1 NA in complex with oseltamivir was constructed using homology modeling. Then, molecular dynamics (MD) simulations, molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations, and MM/GBSA free energy decomposition were used to characterize the binding of oseltamivir with the wild type (WT) and three mutated NAs. Our predictions show that N294S and H274Y, two popular drug-resistant mutations in different variants of NA, still cause significant resistance to oseltamivir. However, the Y252H mutation does not impair the interactions between oseltamivir and A/H1N1 NA. An examination of individual energy components shows that the loss of polar interactions is the key source for the resistance of the studied mutations to oseltamivir. Moreover, free energy decomposition analysis and structural analysis reveal that the N294S or H274Y mutation triggers the large-scale conformational changes of the binding pocket and then impairs the affinity of oseltamivir. We expect that our results will be useful for the rational design of NA inhibitors with high potency against drug-resistant A/H1N1 mutants.

Molecular dynamics simulations approaches for discovering anti-influenza drug

“…Since drug-resistant strains can lead to pandemic outbreak, understating a molecular mechanism for the oseltamivir-resistance is important to improve drug efficacy. Hou and coworkers performed 70-ns of MD simulations for the oseltamivir-resistance of 2009 A/H1N1 strain (Li et al, 2012). They characterized differences in specific interactions of oseltamivir for wild type neuraminidase and for point-mutants including H274Y, N294S, and Y252H.…”

Influenza a (H1n1) and the Resistance to Oseltamivir

“…Historically, human influenza A has been caused by three subtypes of hemagglutinin (H1, H2 and H3) combined with two subtypes of neuraminidase (N1 and N2). However, recently it were identified three other types of hemagglutinin associated with human influenza (H5, H7 and H9), which were previously restricted to influenza subtypes detected in birds (IFPMA, 2009;Pizzorno et al, 2011;Chairat et al, 2012;Karthick et al, 2012;Li et al, 2012).…”

“…In fact, all influenza pandemics that occurred in the last century were caused by descendants of the 1918 virus, in other words, new strains of the same subtype of type A virus. This new strain identified in 2009 contains a combination of genes from the genetic material found in viruses from swine, avian and human influenza, and is continually changing, showing a high transmissible ability among humans (CDC, 2006, CDC, 2009IFPMA, 2009;Rungrotmongkol et al, 2009;Wang et al, 2009;Li et al, 2012).…”

“…Considering this new strain's resistance to amantadine and rimantadine, the protocol of the World Health Organization recommends the use of oseltamivir for the treatment of the disease, instead of zanamivir, considering it is the most effective antiviral agent and due to the greater ease of use, since oseltamivir is available in capsules (Rungrotmongkol et al, 2009;Li et al, 2012). Considering that the replication of influenza viruses reaches its peak in 24-72 hours after the illness onset, oseltamivir, which acts at the viral replication step, should be administered as soon as possible (Flu Virus Today, 2009).…”

“…It is important to have vaccination campaigns, use multi-drug therapies and develop newer neuraminidase inhibitors and other drugs with different mechanisms. In addition, the continuous monitoring of resistance markers is a necessary tool in the prevention and response to an influenza outbreak, since the proper treatment relies on the correct identification of the viral type as well as on the detection of the mutation(s) conferring drug resistance, and the identification of potential resistance sites allows the design of new drugs with better potency (Pizzorno et al, 2011;Hurt et al, 2012;Li et al, 2012;Miyoshi-Akiyama et al, 2012;Shankaran e Bearman, 2012).…”