international journal of pure and applied mathematics ... · molecular visualization and molecular...

“DISCOVERY OF POTENTIAL MTOR INHIBITORS : A COMBINATION

OF VIRTUAL SCREENING AND MOLECULAR DOCKING STUDIES” 1Manikandan.A,

2T. Jayalakshmi

1Assistant Professor,

2 Associate Professor

Dept. of Genetic Engineering

BIHER, BIST, Bharath University

Chennai- 600073.

[email protected]

ABSTRACT

Lung cancer is the leading cause of death in many countries. Non-small cell lung

cancer more common it generally grows and spreads more slowly. Recent, rapid

advances in Molecular Biology have lead to the development of many new agents

that inhibit the activities of specific molecules related to tumor growth, invasion or

metastasis. Several of the protein kinases have been directly implicated in human

ontogenesis by virtue of being over expressed or mutationally activated in cancer

cells. Hence, the protein kinases have been widely considered to represent an

important class of candidates as drug targets for cancer therapy. The mammalian

target of rapamycin (mTOR) also known as mechanistic target of rapamycin.

Rapamycin is a bacterial product that can inhibit mTOR by associating with its

intracellular receptor FKBP12. The FKBP12-rapamycin complex binds directly to

the FKBP12-Rapamycin Binding (FRB) domain of mTOR. Side effects in patients

consuming rapamycin drug severe mood swings, small purple spots over the body

retention, water face allergy and anger. Drug like molecules from drugbank were

used to screen for potential inhibitors by docking in to the active site of mTOR and

also with yielded several docked structures using GLIDE tool. Ten top scoring

ligands, based on the glide score, were selected from the virtual screening .These

drug molecules of are complexed with mTOR was subjected to molecular

simulation studies shows that DB00094 drug molecule can bind effectively into the

International Journal of Pure and Applied MathematicsVolume 119 No. 12 2018, 2225-2238ISSN: 1314-3395 (on-line version)url: http://www.ijpam.euSpecial Issue ijpam.eu

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binding site of mTOR. Thus it is proposed that DB00094 can be a better substitute

of rapamycin.

Introduction

Bioinformatics:

Bioinformatics is the application of information science to the field of

biology. Bioinformatics was applied in the creation and maintenance of a database

to store biological information at the beginning of the “genomic revolution”; such

as nucleotide and amino acid sequences.[1-7] Common activities in Bioinformatics

include mapping and analyzing DNA and Protein sequences, aligning different

DNA and Protein sequences to compare them and creating and viewing 3-D

models for protein structure.

According to the definition given by NCBI, It says that there are three

important sub-disciplines within Bioinformatics: the development of new

algorithms and statistics with which to asses relationships among members of large

data sets; the analysis and interpretation of various types[8-11] of data including

nucleotide and amino acid sequences, protein domains, and protein structures; and

the development and implementation of tools that enable efficient access and

management of different types of information.

Drug design:

Drug discovery research today relies heavily on Bioinformatics to manage the

databases of small molecules that are potential lead compounds, to search Drug

design, also sometimes referred to as rational drug ,[12-15]it is the inventive

International Journal of Pure and Applied Mathematics Special Issue

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process of finding new medications based on the knowledge of the biological

target .

Traditional methods require nearly $800 million and 12-15 years for

introducing a new successful drug into the market. These methods are rapidly

being replaced nowadays with rational drug designing which aims to generate

novel pharmacophores which may act as new successful leads. Rational drug

design in Bioinformatics refers to the use of specialized molecular modeling,

molecular visualization and molecular docking software to accelerate the drug

discovery process insilico based on the exploitation [16-20]of the 3D structural

information of the target molecules and/or the hits obtained via high throughput

screening. Steps involved in rational drug discovery are:

MATERIALS AND METHODS

Maestro Environment

Schrodinger develops stat-of-the-art chemical simulation software for use in

pharmaceutical, biotechnology, and materials science research. since its founding

in 1990.Scrodinger has earned a reputation for its leadership in scientific

environment. Schrodinger products range frrom general molecular modelling

programs to a complete suite of drug design software including both ligand and

structure based methods.[21-26]

Maestro is the linchpin of Schrodinger's computational technology. Far more than

just a visualization program, Maestro also helps researchers organize and analyze

data. Maestro's intuitive interface makes setting up calculations easy and straight

forward. Computed results are automatically returned and incorporated into


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projects for further study. Maestro's vast array of visualization options makes it

possible to glean insight into molecular properties as well as detailed

intermolecular interactions. Maestro is a powerful and versatile molecular

modelling environment,[27-29] and the portal to the most advanced science in

computational chemistry.

GLIDE

GLIDE is a ligand binding program provided by Schrodinger for predicting protein

ligand binding modes. It provides a complete solution for ligand receptor docking.

Glide offers the full spectrum of speed and accuracy from high-throughput virtual

screening of millions of compounds to extremely [30-34]accurate binding mode

predictions,providing consistently high enrichment for every level.

GLIDE is designed to assist in high throughput screening of potential ligands

based on binding mode and affinity for a given receptor molecule.We can compare

ligand scores with those of other test ligands or compare ligand geometries with

those of reference ligand.GLIDE can be used to generate one or more possible

binding modes for a newly designed ligand.protein preparation[35-39] is required

for GLIDE calculation.It can be performed for most protein ligand complex.PDB

structures using protein preparation wizard panel in Maestro.

PREPARING A WORKING DIRECTORY

A working directory is created to keep all the input and output files.After creating

the working directory,start MAESTRO and set the MAESTRO working directory.


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RECEPTOR GRID GENERATION

The receptor grid generation panel helps in grid calculation job.Grid files represent

physical properties of a volume of the receptor(specifically the active site)that is

searched when attempting to dock a ligand.Grid files calculated are used to dock

ligands using GLIDE.[17-21]

STARTING AND MONITORING GRID CALCULATION

After defining the ligand and the active site and setting up constraints,the grid

generation can be started.

LIGAND DOCKING

The glide is used to screen a multiple-ligand file for structures that interact

favorablywith a receptor active site.The receptor grid files calculated is used to

dock ligands.[26-29]Here the ligands used are collected from National Cancer

Institute drug Database.

Discovery Studio

Accelrys has released Discovery Studio 2.5, an advanced computational

chemistry and biology software environment for drug discovery.Accelrys'

scientific operating platform, Discovery Studio 2.5 is an extensible virtual

discovery environment that lets researchers integrate any tool they need to create

solutions that are uniquely tailored to fit their research process.Discovery Studio is

a life science modeling and simulation suite of applications focused on optimizing

the drug discovery process. Discovery Studio makes it easier to examine the

properties of large and small molecules, study systems, identify leads and optimize

candidates. Discovery Studio 2.5 streamlines collaboration and increases research

productivity, addressing areas such as new scientific developments in the area of


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small molecule modelling, fragment-based design, transmembrane protein

analysis, and antibody modelling.

RESULT AND DISCUSSION

DOCKING RESULT

Docking studies were performed to look for potential novel inhibitors of

mTOR.Docking studies were performed using SP GLIDE which do docking of

various conformations of ligand molecules by taking into consideration of various

factors such as ligand binding energy,hydrophobic intractions,hydrogen

bonding,polarity,entropy,RMSD etc.Thus SP Glide score is an overall sum of

scores for favourable as well as unfavourable interaction between the ligand and

the amino acids residues in the binding pocket of Mtor.[31-36]

Based on the SP Glide Score drug bank molecules docked into mTOR were

ranked .It is interesting to find that ten hit molecules were found to be common in

both docking studies. [40-45]


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CONCLUSION

The main goal of the project was to find best common drug for patients affected

with lung cancer due to mTOR abnormality. The target protein selected was

mTOR which was found to be over expressed in majority of the cancers, especially

in lung cancer.

The structure of mTOR was available in Protein Data Bank PDB ID:1NSG. Ligand

molecules for docking were selected from drug bank and prepared for docking.

Docking study was performed using GLIDE. Protein was pre processed and grid

was generated using the structural features of receptor bonding site. The prepared

drug molecules were docked into the grid and binding scores were obtained.

Molecules with best binding score were subjected to simulation studies using

discovery studio.DB00094 was found to have energetically found to bind

effectively with optimal binding confirmations. In fact rest of the nine drug

molecules obtained top scores in docking study also produced significant binding

confirmations with an mTOR receptor site. On the basis of the result can be

proposed direct DB00094 as well as the rest of nine top scoring drug molecules

can be a better substitute of rapamycin which needs to be further confirmed using

clinical studies.


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