Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology
© Zhao et al. 2016
Received: 22 February 2015
Accepted: 10 February 2016
Published: 18 February 2016
The recent outbreak of Ebola has been cited as the largest in history. Despite this global health crisis, few drugs are available to efficiently treat Ebola infections. Drug repurposing provides a potentially efficient solution to accelerating the development of therapeutic approaches in response to Ebola outbreak. To identify such candidates, we use an integrated structural systems pharmacology pipeline which combines proteome-scale ligand binding site comparison, protein-ligand docking, and Molecular Dynamics (MD) simulation.
One thousand seven hundred and sixty-six FDA-approved drugs and 259 experimental drugs were screened to identify those with the potential to inhibit the replication and virulence of Ebola, and to determine the binding modes with their respective targets. Initial screening has identified a number of promising hits. Notably, Indinavir; an HIV protease inhibitor, may be effective in reducing the virulence of Ebola. Additionally, an antifungal (Sinefungin) and several anti-viral drugs (e.g. Maraviroc, Abacavir, Telbivudine, and Cidofovir) may inhibit Ebola RNA-directed RNA polymerase through targeting the MTase domain.
Identification of safe drug candidates is a crucial first step toward the determination of timely and effective therapeutic approaches to address and mitigate the impact of the Ebola global crisis and future outbreaks of pathogenic diseases. Further in vitro and in vivo testing to evaluate the anti-Ebola activity of these drugs is warranted.
KeywordsDrug repositioning Infectious disease Indinavir Sinefungin Binding site similarity RNA-directed RNA polymerase VP24
The recent Ebola outbreak poses a serious threat to human health around the world and has been cited as the largest Ebola outbreak in history . Efficient therapeutics with the ability to cure Ebola infections are yet to be available. Despite recent technological advances, the conventional drug discovery and development process often takes more than 10 years, and costs more than 2 billion dollars to bring a new drug to market . New approaches are urgently needed to deliver medicines to treat Ebola in a timely fashion.
Repurposing safe drugs to be anti-infectious agents has emerged as a novel concept to combat pathogens, and to accelerate drug development [3–7], especially given that the ADME and toxicology properties of approved drugs are already known. Moreover, computational approaches provide an attractive solution in determining potential drug repurposing opportunities, especially where in vitro and/or in vivo screening is difficult or even impossible . It should be noted, however, that several unique challenges are encountered during in silico anti-infective drug repurposing. For example, the successful phenotype-based method  which compares molecular or organismal phenotypes of drug response with those of diseases, has limitations when applied to anti-infective drug development. Notably, it is not trivial to compare drug response and disease phenotype across human and pathogens. Additionally, ligand- and target-based drug repurposing are limited by their under-representative coverage of drug targets in the pathogen genomes . Finally, few virulence-related proteins have characterized ligands, even though their structures are readily available .
Previously, we developed a structural systems pharmacology approach, to identify drug-target interactions on a proteome scale by integrating proteome-wide ligand binding site comparison [11, 12], protein-ligand docking , and Molecular Dynamics (MD) simulation with systems biology modeling [7, 11, 14–21]. Here, we apply this proven successful strategy to reveal FDA-approved and experimental drugs with the potential to inhibit the replication and virulence of Ebola. Here we focused on two main Ebola targets: RNA-directed RNA polymerase (L) and VP24 [22, 23]. RNA polymerase plays a key role in RNA transcription and replication . Thus, the inhibition of RNA polymerase in Ebola may inhibit its replication. Ebola VP24 interacts with human Karyopherin alpha to disarm the human immune system [24, 25]. Thus, the inhibition of VP24 may disrupt the VP24-Karyopherin alpha interaction and reduce the virulence of Ebola. The 3D structure of RNA polymerase was obtained by homology modeling while the druggable binding site of VP24 was explored using MD simulations. The MD simulation has made significant contributions in structure-based drug design in recent years [18, 26–34]. The MD simulation allows us not only to investigate conformational flexibility which plays an important role in molecular recognition,  but also to reveal the potential druggable binding site on the receptor that is not evident from static X-ray structures [18, 26–29, 31, 32]. One thousand seven hundred sixty-six FDA-approved drugs and 259 nucleotide/nucleoside experimental drugs in DrugBank  have been computationally screened against these two targets. As there is not a single docking program performed well for all targets , we used multiple docking software packages to obtain the consensus results to avoid the bias of some docking tools. Our initial screening has identified several promising hits. Specifically, Indinavir, an HIV protease inhibitor, may also reduce the virulence of Ebola based on it high binding affinity to VP24. Additionally, the antifungal drug Sinfungin may inhibit Ebola RNA-directed RNA polymerase through targeting its MTase domain. The detailed binding modes of these promising hits with their respective targets have been determined. The results presented here can be used as a stepping stone to validate the anti-Ebola activity of these drugs through both in vivo and in vitro experimentation, and hence may offer new opportunities to design efficient anti-Ebola therapeutics.
Structural systems pharmacology pipeline
Ligand binding site comparison on a structural proteome scale
Forty thousand four hundred and ninety-one biological units of solved complex structures that are co-crystallized with small molecules with at least five carbon atoms are compared with the predicted binding site of VP24, and SAM co-factor and substrate binding sites in MTase of RdRp using the ligand binding site comparison software SMAP [11, 12, 40]. Top ranked binding sites with their co-crystallized ligands with a p-value < 0.05 are subject to further analysis.
A homology model of O’-2-MTase was constructed iteratively to optimize its binding site conformation. First, human CAP-specific mRNA 2′-O-MTase (PDB id: 4N49) was used as a template to build a homology model whose secondary structure fragments surrounding the SAM binding site are optimized, i.e., no atomic crashes with the putative SAM conformation derived from SMAP. Modeller v9.14  was used in this step. Second, I-TASSER that can build a model from multiple targets was used to add and optimize other fragments: ARG1-ALA26 and SER59-GLU87 to the model. Finally, loops were further optimized using Modeller v9.14. The final model was verified by Verify3D, which determines the compatibility of an atomic model (3D) with its own amino acid sequence (1D) [42, 43], and PROCHECK, which is a program to check the stereochemical quality of protein structures .
The 3D coordinates of 1766 FDA-approved, DrugBank  annotated, non-redundant drugs were downloaded from ZINC database. Additionally, given that a number of nucleotide/nucleoside drugs demonstrated anti-viral properties, 259 nucleotide/nucleoside experimental drugs in DrugBank (updated 2014.03.19) were included in our drug candidates. These drugs were docked to VP24 and RNA-directed RNA polymerase using four docking packages Audodock4 , Autodock Vina , PLANTS , and Surflex . Virtual screening analysis via the AutoDockTools 4 used the following settings in addition to the default docking parameters: ga_num_evals = 1750000, ga_pop_size = 150, ga_run = 20, and rmstol = 2.0. The top confirmation and score for interesting results were output. In Autodock Vina, the research space was redefined by the center coordinate and the size of every dimension of the grid box. The top 1 conformation and score were output. In Surflex, the proto was first obtained by predicting the binding site and protomol. The default parameters are set. The top 1 conformation and score were output. In PLANTS, to dock the drug lib, the screen mode is chosen, the binding site center is redefined as is done for Autodock Vina and the binding site radius is set as 12.5 Å. The top 1 conformation and score were output.
Consensus scoring of protein-ligand docking
For all drug molecules, the corresponding docking scores from each docking tool were ranked. The score correlation was analyzed between two different docking tools by a linear fit. The correlation coefficient is 0.20, 0.43, and 0.61 between the Autodock Vina and Surflex scores, between the Autodock Vina and the PLANTS scores, and between the Surflex and the PLANTS scores, respectively, as shown in Additional file 1: Figure S1. As the correlation is higher between the Surflex and PLANTS scores, the top scored compounds from Surflex and PLANTS were further prioritized. If a drug was ranked within the top 100 by both Surflex and PLANTS, it was selected for further analysis.
We performed a MD simulation to investigate the conformation change of VP24 protein in water. The simulation system was set up using Xleap based on the PDB id: 4M0Q. The TIP3P water box was added with a minimal wall distance of 12.0 Å from the VP24 and 11,237 water molecules were included. The simulation was performed using ACEMD. VP24 was described using the AMBER99SB force field on an NVIDIA GPU machine [50, 51]. The other parameters for the MD simulation were set at 300 K and 1.0 bar and with a 12.0 Å cutoff for the non-bonded interactions. The time step was 4 fs with the SHAKE algorithm . A 200 ns equilibration protocol had been employed, and the trajectory was analyzed using the ptraj plugin. The system reached an equilibration state after 10 ns and the RMSD of the trajectory was shown in Additional file 1: Figure S2. From the equilibrated trajectory, the conformations were clustered based on RMSD. The binding pocket was predicted by Surflex  for the representative conformation of every cluster. The volumes of the binding pocket were determined by CASTp . Finally, the conformation with the largest pocket was chosen.
Results and discussion
Drugs that may disrupt Ebola-human interaction
Putative inhibitors of VP24, along with their structures, docking scores from four docking software packages, and primary targets
Human leukotriene receptor
Human Prostacyclin receptor
Human beta-2 adrenergic receptor
Human prosaglandin F2-alpha receptor
Human prosaglandin F2-alpha receptor
Human Vitamin K-dependent carboxylase
Human DNA topoisomerase 2α
Human 1,1,2 adrenergic receptor
Human prosaglandin F2-alpha receptor
Human prostaglandin E2 receptor
Human prostaglandin E2 receptor
Human angiotension-converting enzyme
Human immunoglobulin receptor
Human prosaglandin F2-receptor
Human beta-1 adrenergic receptor
Human DNA topoisomerase 2α
Human Alpha-1A adrenergic receptor
Human Inosine-5’-monophosphate dehydrogenase
In addition to HIV protease inhibitors, the top 20 ranked drugs; Table 1, (binding modes illustrated in Additional file 1: Figures S3 and S4), are enriched by GPCR-targeted drugs, especially for adrenergic receptors and prostaglandin receptors (p-value = 1.4e-4). Most of these drugs are administered for ocular hypertension or hypertension. Notably, they may serve as additional lead compounds towards the design of selective inhibitors of VP24. Interestingly, like the binding mode of Indinavir in VP24, the binding modes of the other 19 inhibitors, show conserved electrostatic interactions between the respective drug and VP24’s Gln94; shown in Additional file 1: Figure S3a, c, f, i, j, k, n, o, t. It should be noted, in some of the presented drug-target interactions, there are electrostatic interactions from other VP24 amino acids such as: Asp95 for drug hSaleterol Xinafoate (Additional file 1: Figure S3d), Asp115 for drug Tafluprost (Additional file 1: Figure S3k), and Asp99 for drug Benzylpenicilloyl Polylysine (Additional file 1: Figure S3o). Another major residue Gly173 also provide the main hydrogen-bonding interactions for the corresponding drugs as showed in Additional file 1: Figure S3d, e, g, j, m, p–t. Here again, we observe some hydrogen-bonding interactions from other amino acids such as: Ile172 for drug Iloprost (Additional file 1: Figure S3c), Ile98 for drug Remikiren (Additional file 1: Figure S3g), Gly111 for drug Mitoxantrone (Additional file 1: Figure S3i), His177 for drug Misoprostol (Additional file 1: Figure S3l), Thr174 for drug Fosinopril (Additional file 1: Figure S3n), Ile98 for drug Benzylpenicilloyl Polylysine (Additional file 1: Figure S3o), Ile172 for drug Bimatoprost (Additional file 1: Figure S3p), Ile98 for drug Valrubicin (Additional file 1: Figure S3r) and Gln175 for Mycophenolate Mofetil (Additional file 1: Figure S3t).
Importantly, hydrophobic interactions also contribute to the drug-target associations presented in the current study. Specifically, the binding pocket consists of about ten amino acids which form a hydrophobic environment; illustrated by spoked arcs and residue name. Further exploration of these binding modes may provide crucial information towards the design of lead compounds targeting VP24.
Inhibitors of SAM-dependent 2′-O-MTase domain of RNA-directed RNA polymerase
Putative Pfam domains of Ebola RNA-directed RNA polymerase L, along with their annotations, e-value of HHPred alignment, and start and end position of the alignment
mRNAcapping region V
Here, a scan was conducted across 40,491biological units of PDB structures to identify ligand binding sites similar to those present in the modeled 2′-O-MTase using SMAP. Consequently, it is not surprising that SAM binding pockets of multiple MTase were aligned with the 2′-O-MTase model with high statistical significance (p-value < 1.0e–3). The binding pose of SAM in the 2′-O-MTase model was determined by the superimposition of the modeled 2′-O-MTase binding site unto that of the most similar structure; human CAP-specific mRNA 2′-O-MTase from (PDB id: 4 N49). In addition to SAM which is known ligand of MTase, an antifungal drug Sinefungin was identified with high statistical significance (p-value = 1.8e–3).
Putative inhibitors of SAM binding site of 2′-O-MTase, along with their structures, docking scores from four docking software packages, and primary targets
C-C chemokine receptor type 5
nucleoside analog reverse transcriptase inhibitor
DNA polymerase catalytic subunit
In the current study, a single conformation of the receptor structure was used for compound screening using protein-ligand docking. The bias in the scoring functions was minimized by using multiple types of docking software  including Surflex, PLANTS, AutoDock and Autodock Vina. Ensemble docking; a powerful approach which use multiple conformations and is widely used in virtual screening [73–75] allows for flexibility in protein receptors. In the presented high-throughput protocol however, docking is used to identify the initial promising hits. Hence, the priori verification of sampling accuracy will be limited . Moreover, the choice of score function also affects the (ensemble) docking performance. Due to a lack of known reference ligands, it is difficult to determine which conformation ensemble and scoring function are optimal. We will apply the ensemble approach in the near future as more protein-ligand interaction and mutagenesis data become available.
In the current study, we incorporated a proven structural systems pharmacology approach to identify several existing anti-virus and anti-fungal drugs which may be able to target and inhibit critical biological processes such as virus replication and virulence in Ebola. Collectively, in addition to identifying a number of lead compounds which may aid in the design of VP24 inhibitors, our analysis revealed two very promising drug candidates for repurposing: Sinfungin which may inhibit Ebola’s RNA polymerase activity, and Indinavir which may possibly disrupt Ebola-human interactions. Although further in vitro and in vivo experiments are needed to validate these in silico predictions, identification of these candidates is a crucial first step toward the determination of timely and effective therapeutic approaches to address and mitigate the impact of the Ebola global crisis and future outbreaks of pathogenic diseases.
We appreciate the constructive suggestions of the anonymous reviewers and the editor in improving the manuscript. This research was supported, in part, under National Institute of Health Grant R01-LM011986, National Science Foundation Grants CNS-0958379 and CNS-0855217, and the City University of New York High Performance Computing Center at the College of Staten Island.
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