Med Chem Res.2014 March 02. DOI: 10.1007/s00044-014-0964-6

Recent progress and challenges in the computer-aided design of inhibitors for influenza A M2 channel proteins.

Linh Tran, Ly Le.

Ho Chi Minh Int Univ, Sch Biotechnol, Quarter 6,Linh Trung Ward, Thanh Pho Ho Chi Minh, Vietnam.

 

ABSTRACT:

The M2 channel protein has become an attractive target for the design of new drugs against influenza because it plays a crucial role in the replication cycle of influenza A virus. Several adamantane-based drugs have recently been developed to inhibit the activity of the M2 channel and overcome the drug resistance issues observed in amantadine and rimantadine. Computer-aided drug design continues to play a critical role in the drug discovery process in terms of its contribution to the identification and development of new therapeutic agents. Scientists working in this field are currently facing significant challenges with regard to creating novel platforms capable of enhancing our understanding of these proteins, with computational techniques being used to search for new potential drugs against influenza. This review provides a summary of recent progress in drug discovery toward the development therapeutic agents targeting M2 channel proteins. It is hoped that this review will stimulate the development of new strategies for overcoming drug resistance problems and encourage the design of new and improved drugs against influenza A virus.

 

SUPPLEMENT:

The importance of computer-aided drug design has grown significantly in terms of its contribution to the drug development process [1]. Numerous reports have demonstrated that theoretical computational studies, including molecular modeling, molecular docking, molecular dynamics simulations, phylogenetic analysis, quantum mechanical calculations, pharmacophore modeling, QSAR, and bioinformatics techniques can provide useful information for research in drug development [2-4]. Several computational studies have been conducted on the mechanisms associated with M2 channel proteins, and the results of these studies have provided valuable insights into the activity of the M2 channel proteins and enhanced efforts toward the targeting of M2 channel proteins through rational drug design.

Several studies and reviews have recently been reported pertaining to M2 channel proteins that have provided an in-depth understanding of its characteristic features, including its inhibition mechanisms and general structure. The M2 channel protein is activated by low pH and consists of three distinct segments, including: an extracellular N-terminal segment (residues 1–23), a transmembrane (TM) segment (residues 24–46) and an intracellular C-terminal segment (residues 47–97) [5]. The four TM helices create a channel where the His37 residue acts as a pH sensor, the Trp41 residue acts as proton gate, and the Asp44 residue acts as a channel lock [6].

Understanding the mechanisms involved in the inhibition of M2 channel proteins is essential for defining a basic research strategy and conducting a drug development program against this target. We believe that the functional binding site of M2 channel proteins has finally been identified. The amino acid residues inside the M2 channel proteins (i.e., the residues from V27 to G34) have been identified as being particularly important to favorable adamantane inhibition. These results also providing an understanding of why most of the residues inside the M2 proton channel are highly conserved.

The identification and characterization of correlated mutations within the M2 protein could provide an additional source of information with regard to the functional significance of specific residues and regions of the viral proton channel.

The anti-influenza drugs amantadine and rimantadine, which target the M2 channel protein of the influenza A virus, are no longer effective against this virus because of the spread of drug resistance as a consequence of five key mutation points including S31N, L26F, V27A, A30T, G34E, and L38F. The S31N is known to be the most dominant of these mutations, and is present in almost all of the circulating influenza A strain. Phylogenetic study also revealed that several specific positions, including 27, 28, 31, 36, 43, 50, 54, and 57, were involved in mutational correlations clusters [7]. Only a few of these mutational points have previously been described as being significant to the proton transfer mechanism. The roles played by the residues at positions 28, 36, 50, 54, and 57, however, still remain unknown.

We have reviewed several new strategies in computational drug design that used state-of-the-art techniques, as well as a review of recent progress in both computational and experimental studies aimed at identifying new lead compounds for the development of M2 channel inhibitors. The gap in our current understanding of the 3D structures of M2 channel proteins and their inhibition mechanisms has recently been established, which has led to an increase in the amount of research being conducted toward drug resistance and novel rational drug design.

 

Acknowledgments

This work was supported by Vietnam’s National Foundation for Science and Technology Development (NAFOSTED) through grant numbers 106.01–2012.66. The computing resources and support provided by the Institute for Computational Science and Technology, Ho Chi Minh City, Vietnam is gratefully acknowledged.

 

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M2
Fig 1. Model structure of M2 channel protein (A), amantadine (B), and rimantadine(C)

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