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Anwar Gamal Mohamed Frankfort


Anwar Gamal Mohamed Frankfort


 Hepatitis C virus (HCV) infection is a major health problem as

 it can lead to the development of chronic liver diseases such as

 Fibrosis, cirrhosis, and hepatocellular carcinoma in a significant

 Number of infected individuals.1 The current standard-of-care

 Therapy regimen for chronic HCV infection is a combination of

 PEGylated interferon (IFN) and ribavirin along with new

 Protease inhibitors in the case of the genotype 1 clade.

 However, substantial adverse effects together with partial

 Efficacy make it important to develop more potent and safer

 Alternatives.2 After decades of HCV drug development, an

 Interferon-free oral drug regimen is finally on the horizon. In

 This regard, most of the current DAAs undergoing clinical trials

 Act on three key viral targets in the HCV replication cycle:

NS3/4A protease, NS5A protein, and NS5B RNA polymerase.3

 Unlike NS3 and NS5B proteins, no enzymatic function has

 Been identified thus far for the NS5A protein,4 although it is

 Crucial in virus production and has been shown to be involved

 in modulating host immune response, HCV pathogenicity, and

 Replication.4 these findings made NS5A a highly attractive

 target for therapeutic intervention. In this regard, the

 Development of highly potent NS5A inhibitors, which are

 Currently pioneered by Bristol-Myers Squibb (BMS), is serving

as a new therapeutic paradigm that also offers broad HCV

genotype coverage.


The HCV NS5A protein has 447 amino acids and is active as

a homodimer that is organized into three different domains, of

which domain I is the most conserved and noticeably the most

structured domain.5 NS5A can exist in either phosphorylated or

hyperphosphorylated states.6 Adding to these complexities is

the apparent flexibility of the protein. For example, two distinct

crystal structures are currently available for NS5A domain I.7,8

The structure from the group of Charles Rice has an open

conformation,8 in which two NS5A monomers associate with a

large groove in between, while Love’s model had a closed and

tightly bound conformation.7 Both structures lack an important

highly flexible α-helix formed by the N-terminal residues.

Although the two structures represent two distinct dimeric

forms of the same protein, there is no evidence that these two

structures are readily exchangeable from one form to the other.


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However, for convenience, we will use the terms closed and

 open throughout the text below.

 Daclatasvir, developed by BMS, binds selectively in

f1  picomolar concentrations to NS5A.9 The drug (Figure 1A) is

 currently in phase III clinical trials and has been shown to alter

 NS5A subcellular localization,10 block NS5A hyperphosphor-  ylation,6 and inhibit viral RNA synthesis.11 Many related NS5A

inhibitor analogues have been developed based on the chemical

 structure of the parent compound.10,12−14 However, similar to

 Daclatasvir, they still possess a low resistance barrier to several

 mutations. This is expected, as such modifications are not

 directly targeting the protein structural variations due to these

 mutations. To properly address resistance, a detailed evaluation

 on where and how Daclatasvir binds to NS5A will greatly assist

 in future rational drug design of inhibitors against this target.

 The present work demonstrates for the first time, at a

 detailed atomic level, how Daclatasvir and similar dimer

 pharmacophore compounds bind to NS5A using state-of-the-

 art molecular modeling methods combined with the massive

 computational power of the IBM Blue Gene/Q. Our approach

involved 28,871 blind docking simulations of Daclatasvir to 125

dominant NS5A conformations generated from unusually long

molecular dynamics (MD) simulations. The lowest binding

energy model with the best structural fit characteristics

correlates remarkably well with the available experimental

data. This model thus may be useful in guiding the design of

second-generation NS5A inhibitors, which may have less

resistance and/or broader activity against this highly diverse



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2.1. Molecular Dynamics Simulations. Initially, we have

run 3 MD simulations for the open and closed conformations

as well as for a single monomer structure (see Materials and

Methods). The root-mean-square deviations (RMSD) for these

three simulations are shown in Figure 2. The closed (Figure  f2

2A) and open (Figure 2B) conformations have similar features

that are different from that of the monomer structure (Figure

2C). The closed and open simulations fluctuated below 4 Å,


while the trajectory for the monomer structure fluctuated at

almost 6 Å. The open conformation experienced larger RMSD

fluctuations during the simulation time compared to the closed

structure. In particular, at 10 ns, the open RMSD graph reached

its maximum value before descending back to a more rigid

conformation followed by a gradual transition to the final

equilibrated conformation, which spanned the last 45 ns of the

simulation. The same, but minor, behavior was noted in the

closed structure. For the monomer simulation, however, the

structure seems to have a stable conformation, which was

 reached progressively with no obvious transitions through

 intermediate conformations. The high flexibility of the three

 structures in general can be attributed to the highly flexible N-

 terminal helices. This is apparent in Figure 1B, which shows the

 atomic fluctuations per residue for the monomers constituting


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the closed and open structures compared to the single 

monomer simulation. For the five monomers (two for the

open structure, two for the closed structure, and one for the

single monomer), the most flexible region was the N-terminal

α-helix. The trajectory for the single monomer simulation is

aligned and shown in Figure 1C. Although the α-helix adopted

a wide range of different conformations, the rest of the protein

structure seems to be rigid and barely fluctuated around adistinct stable conformation.

Anwar Gamal Mohamed research

Anwar Mohamed Frankfort

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