Accepted Manuscript

Title: Clustering based drug-drug interaction networks for

possible repositioning of drugs against EGFR mutations:
Clustering based DDI networks for EGFR mutations

Authors: Anum Munir, Sana Elahi, Nayyer Masood

PII: S1476-9271(17)30871-X
DOI: https://doi.org/10.1016/j.compbiolchem.2018.04.011
Reference: CBAC 6843

To appear in: Computational Biology and Chemistry

Received date: 17-12-2017

Revised date: 30-3-2018
Accepted date: 15-4-2018

Please cite this article as: Munir, Anum, Elahi, Sana, Masood, Nayyer, Clustering
based drug-drug interaction networks for possible repositioning of drugs against EGFR
mutations: Clustering based DDI networks for EGFR mutations.Computational Biology
and Chemistry https://doi.org/10.1016/j.compbiolchem.2018.04.011

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 Clustering Based Drug-Drug Interaction Networks for Possible

Repositioning of Drugs against EGFR Mutations: Clustering

Based DDI Networks for EGFR Mutations

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Anum Munir1, 3*, Sana Elahi1, Nayyer Masood1,2

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1
Department of Bioinformatics and Biosciences, Capital University of Science and

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Technology, Islamabad Pakistan,

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Department of Computer Science, Capital University of Science and Technology,

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Islamabad Pakistan,
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3
Bioinformatics International Research Club, Abbottabad, Pakistan
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Corresponding Author: Anum Munir, Department of Bioinformatics and Biosciences,

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Capital University of Science and Technology, Islamabad, 44000, Pakistan,

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Email: anummunir786@yahoo.com, Contact Number: +923348958178

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Graphical abstract

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Highlights:

 The strong interactions among the drugs are deemed as synergistic

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 The synergistic effect arises when the interactions cause an expansion in the effect
of either of the drug molecule.
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 The network structure is usually portrayed by a high modularity

 Modularity is directly connected to the links, which demonstrate the drug
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interactions
 The centrality analysis is conducted to determine the strong interactions among the
drug compounds
  Toxic doses are frequently administered as LD50 values in mg/kg of the body
weight.
 The LD50 is the average lethal dose
 Different types of interactions are observed in each docked complex
 Drug-like properties based on Lipinski rule can be utilized as a part of the drug

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repurposing
 drug-like properties based on Lipinski rule can be utilized as a part of the new drug-

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drug interaction discoveries.

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Abstract
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EGFRs are a vast group of receptor tyrosine kinases playing an important role in a number
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of tumors, including lungs, head and neck, breast, and esophageal cancers. A couple of

techniques are being used in the process of drug design. Drug repositioning or repurposing
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is a rising idea that consists of distinguishing modern remedial indications for officially
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existing dynamic pharmaceutical compounds. Here, a novel approach of analyzing drug-

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drug interaction networks, based on clustering methodology is used to reposition effective

compounds against EGFR mutations. Data about 2062 drugs are obtained, and mining is
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performed to filter only those drugs which fulfill Lipinski rule of five. Clustering is

performed, and DDIs are built on the clusters to identify effective drug compounds. Only
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1052 compounds fulfill Lipinski rule. 12 clusters are formed for 1052 drugs compounds.

DDIs are developed for each cluster. Only 15 drugs are suggested to be more effective

assuming strong interactions in a DDI.

Keywords: Clustering, Drug-drug interaction, EGFR, Lipinski rule, Repositioning

Introduction

The epidermal Growth Factor receptor (EGFR) group of receptor tyrosine kinases (TKs),

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also known as the HER or ErbB family comprises four members HER1 (ErbB1), HER2

(ErbB2), HER3 (ErbB3) and HER4 (ErbB4) that direct numerous metabolic, physiological

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and developmental pathways (Gazdar, 2009) Stanley Cohen, a scientist, found EGFR 25

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years ago and explained its part in cell development (Seshacharyulu et al., 2012). The

EGFRs are a vast group of receptor tyrosine kinases playing an important role in a number

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of tumors, including lungs, head and neck, breast, and esophageal cancers. EGFR and its
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members are the significant contributors of signaling cascades, thus, regulate development,
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signaling, migration, adhesion, development, and survival of tumor cells. Because of their
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multidimensional role in a number of malignancies, EGFR family has risen as an important

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candidate for the treatment of cancer (Grandis and Sok, 2004).

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Particularly the abnormal movement of EGFR has appeared to play a key role in the

development of tumor, where it is involved in the various cellular reactions, including

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apoptosis and cell proliferation (Wells, 1999). Nowadays, a lot of investigative studies are
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being done on EGFR ligand binding inhibition through the design of many antibodies and

therapies (Lin et al., 2003). A number of techniques are being used in the process of drug
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design. Drug designing is a necessary piece of most medication disclosure programs

(Mountain, 2003) and is the real subject of research for some academic labs (Anderson,

2003). Cancer targets can be irritating because the targets are regularly physical cell
mutants of proteins that manage fundamental cell functions, bringing about the loss of a

general function. Obviously, it is irritating for a small inhibitor to potentiate the recovery of

a general function (Kaelin, 1999).

Drug repositioning or repurposing is a rising idea that comprises of distinguishing new

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remedial indications for officially existing dynamic pharmaceutical compounds (Udrescu et

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al., 2016; Sleigh et al., 2010; Munir et al., 2016). The rise of huge information and

examination has impelled the utilization of computational methodologies in numerous parts

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of pharmacology and medication configuration, including drug repurposing. In fact,

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computational models are utilized to reveal drug interactions, which were not found during

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clinical trials (Tatonetti et al., 2012), or to anticipate drug security (Egan et al., 2004).
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Utilizing In-silico devices make a visual and natural framework for representing the
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interactions (Lewis, 2010), in this manner helping medicinal and pharmaceutical practice.

A drug-drug interaction (DDI) is an unpredictable system in which the nodes represent

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drugs, and the links between them correspond to the drug interaction, relationships (Polesk
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et al., 2011; Karlgren et al., 2011). Clustering methodologies are utilized to build DDI that
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proposes conceivable repositioning (Nugent et al., 2016). Here in this research work, the

same technique of clustering is applied to build the DDI to perform drug repositioning
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against the EGFR mutations. Though, current research proposes that interaction evidence

from DDI alone can be used to calculate physiological effects of the drug and therefore,
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achieve drug repositioning

Material and Method

In this section, a novel procedure of drug repositioning against EGFR gene is proposed.

This procedure is based on the clustering of drug properties and development of DDIs.

First, the procedure of clustering is explained then the method of building DDIs and

repositioning of drugs based on DDIs is explained.

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Collection of Drugs Property Data

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The data of commercial compounds, which can be used in the treatment of EGFR

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mutations in various cancers, were obtained from Zinc database, through virtual screening.

The zinc is a database of commercial drug compounds; in addition to the chemical

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structures of drug compounds, it also gives information about the drug-like properties of
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the chemical compounds. Virtual screening is a computational method used in the parts of
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drug innovation and improvement to discover collections of small ligands, which can
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appropriately bind to their target proteins or enzymes (Raster, 2008; Rollinger et al., 2008).
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The data is comprised of about 2052 records of the drug compounds, consisting of the
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chemical properties such as; Drug Zinc ID, Log P, Molecular weight (Mw), Hydrogen bond

donors(HBD), Hydrogen bond acceptors(HBA), Rotatable bonds (RB), A-polar

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dissociation and Polar dissociation.

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Mining of Data based on the Lipinski rule of five

Initially, the data consisted of all the drug's compounds, which can be used to treat EGFR
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mutations. Most of the records lists contain obsolete drugs, which are toxic in nature and

have a lot of side effects. The data was sorted, and mining was performed to filter those

drug compounds that do not fulfill Lipinski rule of five and obtained only 1050 drugs
fulfilling the Lipinski rule of five. This rule demonstrates that drug-like compound must

have Mw no more than 500 Daltons, less than five HBD, less than ten HBA, and logP

ranges between 0 -5 (Gemma et al., 2006).

Clustering of Drug compounds

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Simple K means clustering was performed on the drug's information data in the Weka tool.

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WEKA is a prevalent machine learning work surface, contains applications of algorithms

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for clustering, classification, and association rule mining, along with the graphical user

interface and visualization services for data investigation and evaluation of an algorithm

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(Bouckaert et al., 2010). K-means is one of the simplest unsupervised learning algorithms
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used to solve the renowned clustering problem. This process follows a simple and easy way
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to classify a given data set (x¬¬1, x2, x3…… xn) into a certain number of clusters, usually
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K clusters, (K ≤ N) (Macqueen 1967). The optimal number of cluster K(n) was determined
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using Elbow method given by Kodinariya and Makwana (2013) where K is the number of
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clusters and n is the data set.

Drug-Drug Interaction Network generation

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Drug-Drug interaction networks were built on the K clusters to determine the strong
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association between drug compounds within each cluster with the assistance of Gephi 0.9.1.

It is a principal tool for the visualization and analysis of large networks designed by
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Andrew (2012). Each network consists of the set of vertices V and edge E, The average

path length L, The degree D of nodes, Network Density, and modularity classes. Modules
are particular parts of a system where the density of edges is fundamentally higher than

expected. For each network the L calculated by the formula

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𝑙=
𝑛(𝑛 − 1)

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Where n is the number of vertices in the graph. The average clustering coefficient was

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calculated by the formula

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|𝐸𝑗, 𝑘 ∗ 𝑉𝑗, 𝑘𝑁|
𝐶=
𝐾𝑖(𝐾𝑖 − 1)

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Where E is the edge, V is the vertex, N is the total number of nodes and Ki is the neighbor
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vertices. The strong interactions among the drug compounds in each cluster were observed.
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The modularity was calculated by the formula
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𝑖 𝑑
𝑀 = Ʃ[ − ( ) ^2]
𝐸 2𝐸
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Where E is the number of edges in the network, i represent the number of strongly

connected edges, and d is the degree of a node. The drug compounds, which demonstrated
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stronger interactions in each cluster, were selected for further studies.

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Mining of strongly interacted drugs to select most suitable drugs

The strongly interacted drugs obtained through the DDI network were further analyzed for
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their toxicity level, the drugs having lethal toxic classes were mined, and only those drugs

were selected, which demonstrate lower toxic classes.

Repositioning of strongly interacted drugs

The drug compounds, which demonstrated stronger interactions and low toxic classes, were

suggested to be used in combination with each other to achieve maximal results during the

treatment. DDIs reflect the intervention of several behaviors of the drug. In order to

understand potential repositioning, the strategy explained in this paper depends on the

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behavioral interactions between drugs rather than the structural similarities characterized by

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chemical-structures interactions or drug-target interactions. Therefore, to reduce the

complexity required by drug repurposing, it is suggested that this interactive perception can

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be integrated with the complementary structural perception (Bastian et al., 2009).

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Results

Cluster Generation
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The Drug property data obtained from the Zinc database were filtered based on a Lipinski

rule of five. Among the 2062 chemical compounds, only 1052 compounds fulfilled the
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Lipinski rule of five and were selected for further analysis. By using the clustering
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methodology for grouping the similar chemical compounds, K-means algorithm was used.

12 K clusters were identified by Elbow method and built for 1052 drug compounds. The
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clusters were built for all the properties fulfilling Lipinski rule, shown in Fig 1. Each cluster
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contains only those drug compounds, which are similar to each other, based on their

properties, and are represented by different colors.

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Development of Drug-drug Interaction networks

12 distinctive DDIs were built on the clustered data to find strong interacting drugs. In each

DDI every node represents a distinct drug. A connection between the two drugs relates to
the interaction between them according to the similarity of their properties. No data with

respect to the structural properties of these drug compounds is utilized throughout the

procedure. As each cluster contains similar drugs, therefore; the strong interactions among

the drugs demonstrate them as synergistic, because this type of interactions provides

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information about the functional profile of a drug cluster. At the point; when the

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interactions cause an expansion in the effect of either of the drug molecule the interaction is

known as a synergistic effect. An "additive synergy" happens when the last effect is

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equivalent to the sum of the effects of the two drugs. A point occurs when the final effect is

substantially more prominent than the sum of the two effects this is called enhanced

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synergistic effect (Qato et al., 2016). The DDIs are shown in Fig 2.
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The network 1 consists of 338 nodes and 562 edges; the network 2 is comprised of 205
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nodes and 305 edges. Similarly; 373 nodes and 569 edges in network 3, 509nodes and 809

edges in network 4, 404 nodes and 592 edges in network 5, 238 nodes and 342 edges in
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network 6, 424 nodes and 628 edges in network 7, 480 nodes and 799 edges in network 8,
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549 nodes and 914 edges in network 9, 328 nodes and 453 edges in network 10, 318 nodes
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and 428 edges in network 11, 470 nodes and 710 edges in network 12 were identified. It

was observed that network 9, 8, 4, and 12 contained maximum interacting drugs and edges
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as compared to other DDIs

Modularity and average clustering coefficient analysis

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Modularity classes were calculated for each DDI. Distinct colors were assigned

automatically, to the nodes based on modularity. The network structure is usually portrayed
by a high modularity, both in the bipartite network and in their projections, showing that

topology is exceptionally distinct from an arbitrary network, and that it contains a rich and

heterogeneous modular structure (Zahoránszky-Köhalmi, 2016). The modularity based

coloring is steady. This outcome is a result of modularity being a decent indicator of

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properties and usefulness of chemical compounds (Qato et al., 2016). Additionally,

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modularity is directly connected to the links, which demonstrate drug interactions. The

average (Avg) degree, network density, modularity, Avg path length, and the Avg graph

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clustering coefficients are shown in Table 1.

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Network Centrality Analysis

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Centrality analysis was performed to determine the strong interactions among the drug
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compounds, drugs that were most susceptible to DDIs link to the nodes with the largest
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network centrality values were confirmed.

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Repositioning of Strongly Interacted drugs

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From each DDI, drugs representing the strong interactions were selected, and a last drug-
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drug interaction network was built, based on the data consisting of strongly interacted drug

compounds. The last DDI is shown in Fig 3.

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The final DDI network contains 290 nodes and 416 edges. Again, the same procedure was
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used to assign different colors to the nodes, average degree, network density, modularity,

average path length, and the average graph clustering coefficients were calculated and the

drug compounds that demonstrate strong interactions were selected. Finally, only 15 drugs
represent stronger interactions to each other. Values such as network density, clustering

coefficient, etc., of the final DDI network, are shown in Table 2.

The chemical properties of strongly interacted drugs found in the final DDI network,

fulfilling Lipinski rules of five are shown in table 3.

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The 15 strongly interacted results were further analyzed for the toxicity; Toxic doses are

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frequently administered as LD50 values in mg/kg of the body weight. The LD50 is the

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average lethal dose implying, the dose at which 50% of test subjects die upon introduction

to a compound. The drugs with fewer toxic values are shown in Table 4.

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Only 11 drugs were lying in the toxicity class 4 and 5, both are non-toxic classes; Four
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drugs were mined due to higher toxic values, based on results; these 11 strongly interacted
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drugs are suggested to be used in the treatment of EGFR, and can be given to patients in

combination with each other to achieve maximal results of treatment.

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This entire information presents the case for recouping various drug properties, for
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remaking some known drug repositioning, and the arrangements of conceivable drug-like
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properties based on Lipinski rule can be utilized as a part of the drug repurposing or in new

drug-drug interaction discoveries. This methodology can overcome numerous

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pharmacological issues as well as known repositioning, using only information about DDIs
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Discussions

The clustering based, DDI network strategy introduced in this research work is portraying

drug interaction potential for the treatments of certain diseases. On the other hand, a few
parameters like modularity, path lengths, clustering coefficient, etc.., can distinguish those

drugs which have the most noteworthy potential for DDIs. By utilizing twofold clustering

techniques for DDI networks and drug repositioning, one can, undoubtedly, filter out useful

drug molecules from the jumble of drug compounds. There is a high likelihood that, the

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pharmacological properties by this twofold clustering strategy can be affirmed, these 15

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drug compounds can be additionally examined with in vivo and in vitro methods, to affirm

the conceivable repositioning or new interactions. The DDIs usually reflect the impedance

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of drug practices. The system clarified in this paper depends on the behavioral interactions

between drugs instead of the basic structural or drug target associations. It is proposed It is

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proposed by Nacher and Schwartz (2012) that this behavioral point of view can be
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coordinated with the structural perspective for better outcomes.
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Nowadays, a lot of network-based methods are being developed; these methods have,

likewise, being utilized to distinguish drug candidates suitable for repositioning (Newman,
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2003). For example, Chiang and Butte processed drug-drug similarity mechanism to
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recognize drug repositioning applicants (Zahoránszky et al., 2016), whereas some other
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used either drug-drug similarities (Wu et al., 2013; Chiang and Butte, 2011) or both drug-

drug and disease-disease similarity approaches (Yang and Agarwal, 2011; Cheng et al.,
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2012; Yutuka et al., 2013). Nonetheless, the vast majority of these methodologies is either

drug driven, disease driven or symptoms driven. Here in this research work, a DDI
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approach is utilized based on the clustering strategy to recognize the best chemical

compounds, which can be utilized to treat EGFR mutations.

Several anticancer drugs have been created. Many patients with strong tumors still show the

poor prognosis. Hence it is critical to decide the proper utilization of such medicines

clinically. Several anti-cancer agents are being used. Various combinations of treatment

regimens have turned out to be effective (Assaf et al., 2011) and are broadly concerned

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with the introductory treatments for cancers (Keiser et al., 2009). However, at present, the

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effect of these treatments on enhancing persistent survival stays in a far away (Bonomi et

al., 2000; Schillar et al., 2002; Shepherd et al., 2013). Therefore, the method of identifying

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effective drugs by using DDIs based on clustering methods will be proved fruitful and will

show more satisfactory results.

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Conclusion N
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This approach to predict novel drugs by representing drug-drug interactions and using the
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clustering methodology, not just prompted the proposal of drug repositioning, but
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hopefully, permits additional knowledge into them. The predictions produced for a strongly
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interacted drug exhibit that this approach can viably recognize new indications and more

compelling drugs to treat EGFR mutations. 12 clusters were formed for 1052 drugs
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compounds. DDIs for developed for each cluster. Only 15 drugs are suggested to be more

effective based on strong interactions in a DDI and can be given in the combination to
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achieve maximal benefits. However, this is an In-silico study. Further examinations can be

performed in-vivo and in-vitro to confirm the efficacy of these suggested drug compounds.
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Acknowledgments
The Authors are grateful to Bioinformatics International Research Club Abbottabad for

providing a platform to conduct research.

Conflict of Interests: None of the authors have any challenging conflict of interests

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Wells A.( (1999). EGF receptor. Int J Biochem Cell Biol. Vol. 31, pp. 637–43. [PubMed:

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Wu, C., Gudivada, R. C., Aronow, B. J., & Jegga, A. G. (2013). Computational drug
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repositioning through heterogeneous network clustering. BMC Systems Biology, Vol. 7,

No. 5, S6.
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Yang L, Agarwal P. (2011). Systematic Drug Repositioning Based on Clinical Side-

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Effects. PLoS ONE, Vol. 6, No. 12, :e28025.

EP

Yutaka Fukuoka DT, Hisamichi Ogawa. (2013). A two-step drug repositioning method

based on a protein-protein interaction network of genes shared by two diseases and the
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similarity of drugs. Bioinformation Vol. 9, No. 2, pp. 89-93.

A

Zahoránszky-Köhalmi, G., Bologa, C. G. & Oprea, T. I.(2016). Impact of similarity

threshold on the topology of molecular similarity networks and clustering outcomes.

Journal of cheminformatics, Vol. 8, No. 1.

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A

Figure 1: The number of clusters formed by using every property of the 1052 drug compounds

Figure 2: Drug-drug interaction networks built for each cluster, small spheres represent drugs,

interactions between the drugs compounds are represented by dotted lines, whereas the strong
interactions are represented by solid lines. The strong interactions are represented by solid lines of

purple, green blue and orange color among the nodes.

Figure 3: The Drug-drug interaction network generated on strongly interacted drugs data. The

stronger interactions are shown by dark green color edges, which were selected for further analysis.

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RI
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M
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A
 Table 1: Degrees, Densities, path lengths, and modularity values predicted for each Drug-drug

Interaction network

Average Network Graph Modularity Clustering Average

Degree diameter Density Coefficient Path

PT
length

RI
Network 3.213 5 0.005 0.587 0.021 0.9821

SC
Network 2.967 2 0.007 0.627 0.01 1.036

U
2

Network 3.051 2 0.004

N 0.59 0.001 1.039
A
3
M

Network 3.179 2 0.003 0.554 0.001 1.046

4
D

Network 2.931 2 0.004 0.598 0.002 1.036

TE

Network 2.874 2 0.006 0.617 0.001 1.063

EP

6
CC

Network 2.923 3 0.004 0.617 0.002 1.071

7
A

Network 3.329 2 0.003 0.595 0.002 1.047

Network 3.339 4 0.003 0.595 0.002 1.161

 9

Network 2.762 1 0.004 0.61 0.021 1.0

10

Network 2.937 1 0.005 0.62 0.001 1.0

PT
11

RI
Network 3.021 2 0.003 0.595 0.002 1.095

12

SC
U
Table 2: Degrees, Densities, path lengths, and modularity values predicted for the final Drug-drug

N
Interaction network
A
Average Network Graph Modularity Clustering Average
M

Degree diameter Density Coefficient Path

length
D

Final 2.938 1 0.005 0.54 0.021 1

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Network
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Table 3: The Properties of the drug compounds, fulfilling Lipinski rule of five
CC

Selected Drugs XlogP Hydrogen Hydrogen Molecular Rotatable

bond donors bond weight bonds

A

acceptors

ZINC66252027 1.6 3 7 364 6

ZINC29128766 3.83 3 9 466 9

ZINC29043935 4.75 3 9 497 9

ZINC28903156 1.75 4 9 454 6

ZINC28903151 1.89 4 9 454 6

ZINC28903146 1.86 4 9 454 6

ZINC28817149 3.41 4 9 499 7

PT
ZINC29128814 3.19 4 9 426 9

RI
ZINC28901061 3.13 4 8 446 9

ZINC34642910 3.43 4 8 448 9

SC
ZINC34800033 3.47 4 8 461 9

ZINC64564748 4.41 4 7 472 9

U
ZINC29128958 3.54 4 9 493 9

ZINC26983604

ZINC29198958
1.56

1.53
5

3
N 9

7
397

365
9

7
A
M

Table 4: The drugs which lie in the lower toxic classes

D

S.no Structure Zinc ID Predicted Toxicity

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LD50 class

1
EP

ZINC66252027 1800 mg/kg Toxicity class

4
CC
A
2 ZINC29128766 1000 mg/kg Toxicity class

PT
3 ZINC29043935 1000 mg/kg Toxicity class

RI
SC
4 ZINC28903156 1000 mg/kg Toxicity class

U
4
N
A
M

5 ZINC28817149 2500 mg/kg Toxicity class

5
D
TE
EP

6 ZINC29128814 1000 mg/kg Toxicity class

4
CC
A
7 ZINC28901061 1600 mg/kg Toxicity class

PT
8 ZINC34642910 3160 mg/kg Toxicity class

RI
SC
9 ZINC64564748 1000 mg/kg Toxicity class

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4
N
A
M

10 ZINC29128958 1000 mg/kg Toxicity class

D

4
TE
EP

11 ZINC29198958 5000 mg/kg Toxicity class

CC

5
A