USER’s GUIDEscfbio-iitd.res.in/Setup_Inventus/USER_GUIDE- INVENTUS V1... · 2020-01-14 · 7...

1 INVENTUS v1.0 USER GUIDE

INVENTUSTM β v1.0

USER’s GUIDE

InventusTM

Version 1.0 Rev. β

October 2014

A product by

Novo Informatics Pvt. Ltd.

IIT-D based Company

New Delhi, India


Copyright © 2014 Novo Informatics Pvt. Ltd., All rights reserved.

Inventus is a trademark of Novo Informatics Pvt. Ltd.

The following are either registered trademarks or trademarks of

Microsoft Corporation in the United States and/or other countries:

Microsoft Visual Studio 2010 Professional, Microsoft Excel.

pkExpress is a propertiary of G2 Research, Inc (USA)

Adobe Acrobat is a registered trademark of Adobe Systems Incorporated.

Intel Pentium is a registered trademark of Intel Corporation.


Chapter 1

INVENTUS™ is a comprehensive software suit

developed and validated to predict relevant

computational studies like protein structure optimization,

virtual high throughput screening, docking, geometry

calculations and ADME characteristics of potential

drugs. The software can be deployed as a PC desktop

application or as a large compute engine.

INVENTUSTM

major module includes the following:

PocketDetector

HitsGen (Virtual High throughput Screening)

BioAff (Binding energy Calculator)

NovoDocker (Docking)

PharmoPredicta (ADME based model along with

sensitivity analysis)

The Need for INVENTUSTM

Historically, inappropriate calculations and accuracy in

results have been a major reason for the failure of

compounds in the later stages of drug development. This

fact was largely due to an inability to identify and rectify

right candidate as well as poor pharmacokinetic

characteristics present in many lead series accepted for

lead optimization. With the adoption of High throughput

screening, Docking & MD simulations, combinatorial

chemistry, and parallel synthesis in drug discovery, the

need for early information on the absorption,

metabolism, distribution and elimination (ADME) of a

compound has become increasingly important in the lead

selection and optimization process. This need has driven

the development of in silico models for predicting initial

hits molecules against selected targets and to

characterize the ADME characteristics of a compound at

early stages. Using this information, computational

biologist and chemists steer away complexes using

additional information from INVENTUSTM

.

The INVENTUSTM

predictive models were trained using

a diverse data set of public repository data as well as


internally generated in vitro data, human

pharmacokinetic data from clinical trials, chemical

structure, and development successes and failures. The

models were internally and externally validated to

benchmark their performance. The following is a brief

overview of the models and capabilities of

INVENTUSTM

. For more information, see the chapters

following this introduction.

INVENTUSTM version 1.0 InventusTM is a complete drug discovery suite which

was based on the state of the art technology

developed by supercomputing facility for

bioinformatics (SCFBIO Lab) at Indian Institute of

Technology Delhi (India). InventusTM aims on

providing integrated software solutions that truly

meet its customer‟s needs. It empowers researchers

around the world to achieve the goal of improving

human health and quality of life through advanced

computational techniques which can help

experimental biologist to identify potential leads.

HitsGenTM Computational drug discovery is expensive process

in both cost and time. The prime need in the virtual

screening process is the speed and accuracy, where

speed in terms of time required in screening and

accuracy in terms of finding true positives. In nearly

all cases of virtual screening there are both false

positive and true positive in the screened compound

pool of libraries. Inventus virtual high throughput

screening is based on the protocol developed, which

was successfully able to remove false positive from

the screened molecules. Molecules can be screened

using customized library as well as embedded

library (size ~ 40mn).

The screening methodology is based on structural

and physicochemical descriptors of small molecule

and functional groups lining the active sites of

bimolecular targets, for estimating binding affinity

with significantly reduced time, facilitating a rapid

scanning of large databases in the search for hit

molecules.


NovoDockerTM

Molecular docking is a computational procedure

that predicts the non-covalent binding of

macromolecules or, more frequently of a

macromolecule (receptor) and a small molecule

(ligand) efficiently. The key characteristic of a good

docking program is its ability to reproduce

experimental binding poses of ligand. To test this

ability the ligand is taken out of X-ray structure of

its protein-ligand complex and docked back into its

binding site. The docked binding pose was

compared with the experimental binding pose, and a

root mean square (RMSD) between the two is

calculated, if the calculated RMSD between these

two poses were under 2Å a then the prediction of

binding pose was considered as successful for a

particular protein-ligand complex.

BioAffTM

Binding energy calculation of protein-ligand

complex. Inventus binding energy employs a

computationalluy fast protocol for predicting

binding affinities of non-metallo protein-ligand

complexes.The protocol was based on a all atom

energy based empirical scoring function comprising

electrostatics, van der Waals ,hydrophobicity and

loss of conformational entropy of protein side

chains upon ligand binding

PharmoPredictaTM

Inventus pk Express has been bought from G2 Research

(US based company). The InventusTM pkEXPRESS

physiological models were trained using a diverse

data set of internally generated in vitro data, human

pharmacokinetic data from clinical trials, chemical

structure, and development successes and failures.

The models were internally and externally validated

to benchmark their performance. The following is a

brief overview of the models and capabilities of

Inventus pkEXPRESS.


Physiological Absorption Model Developed in collaboration with five major

pharmaceutical companies, the patented (1) Absorption

Model in pkEXPRESS predicts human intestinal

absorption. The system's patented dispersed plug flow

model of absorption simulates human physiology and

accounts for the regional solubility, regional

permeability, intestinal surface area, and fluid flow in

the gastrointestinal tract. Optimized using internally

generated in vitro data, intravenous and oral

pharmacokinetic clinical data, and chemical structures,

The 67 drugs in the Absorption Model training set span

19 different therapeutic classes and include development

successes and drugs that failed clinical trials.

Compounds in the training set were selected so that a

broad range of solubility, permeability, transport

properties, and extent of absorption was represented.

Using dose, chemical structure, solubility, Caco-2

permeability, and efflux (optional input), the Absorption

Model predicts the extent of absorption, absorption rate,

mass absorbed, soluble mass, insoluble mass, and

intestinal drug concentration of potential drugs.

Physiological Metabolism Model The InventusTM

pkEXPRESS physiological Metabolism

Model was designed and validated to predict the first

pass metabolism and bioavailability (FH) of potential

drug compounds. The parallel tube liver flow model

simulates first pass metabolism using a predicted

absorption rate from the Absorption Model, protein

binding, and metabolic stability of a compound. The

Metabolism Model was optimized using a training set of

internally generated in vitro data, literature and

collaborator pharmacokinetic clinical data, and chemical

structures. The 82 data points from 61 drugs in the

Metabolism Model training set, representing 37 different

therapeutic classes, have a broad range of Km, CLint,

protein binding, and extent of metabolism. By

incorporating the Km as well as the CLint, our

physiological model accounts for the extent of

metabolism when metabolizing enzymes become

saturated. This is an important phenomenon that is often

ignored by models, especially by those making a linear

assumption. The Metabolism Model in Inventus

pkEXPRESS incorporates the Michaelis-Menten

equation to describe turnover kinetics and successfully


predicts FH for compounds, whether they demonstrate

linear or non-linear turnover kinetics, without

overestimating first pass metabolism.

Physiological Distribution & Elimination Based on the Distribution and Elimination Model

published by Kawai, et. al. (J. Pharm and Biopharm Vol.

22 No.5 1994), the Distribution and Elimination Model

in Inventus pkEXPRESS uses published human

physiological blood flow rates and organ and tissue

volumes to predict the plasma level time curve (PLTC),

Cmax, tmax, and area under the curve (AUC) of a

compound. From the PLTC, other relevant

pharmacokinetic parameters such as Vss, CLtot and, t1/2,

for a one or two compartment micro and macro-

constants model can be calculated.

The model was trained using intravenous and oral

pharmacokinetic data from 147 published and

proprietary clinical studies. The model predicts the

distribution and elimination of potential drugs, uses

protein binding, a red blood cell partitioning ratio, and

either the predicted rate of absorption or metabolism

obtained from the Absorption and Metabolism Models

respectively.

Sensitivity Analysis Sensitivity analysis, (i.e. how sensitive FH and FDp are

to changes in the Caco-2 permeability or dose), can be

used to investigate the impact various input parameters

have on the Inventus pkEXPRESS predictions. By using

the Inventus pkEXPRESS two dimensional sensitivity

analysis, you can quickly determine the effect of

interdependencies between parameters on the outcome.

This information on parameters can help to assess which

assays are the most useful in identifying critical

properties on which to focus lead optimization resources,

or to identify compounds with ADME liabilities that are

unlikely to be overcome.

System Requirements Minimum Computer Specifications:-

Intel® Dual Core processor

2 GB RAM

Inbuilt 8MB Graphic Card


Recommended Computer Specifications:-

Intel® i3 processor machine

4 GB RAM

500 MB graphic Card or 1gb Graphic Card(For

HD Resolutions)

Other Operation system & software’s required:-

Microsoft® Windows 7/8 Home basic/Ultimate

Adobe® Acrobat ® Reader version 5.0 or higher

Microsoft Office 2007 or higher version

Installation What you will find on the CD-ROM

The following are included on INVENTUSTM

CD-ROM

Inventus running application

Inventus pkExpress application

Associated default parameters files

The User‟s Guide in pdb format

Validation report in pdb format

Test data to verify proper installation for

PharmoPredicta only

Installation Procedure When you insert the INVENTUS CD-ROM into your

computer drive, the Install Shield Wizard should start

automatically. (If not, open Windows Explorer and

navigate to the CD-ROM. Double-click on „setup.exe‟ to

start the Install Wizard.) The Wizard will guide you

through the setup process. After installation is complete,

you will be asked to restart your computer. If you are

using trail version it will specify number of days and

once trail is finished and you wish to continue, you need

to insert license key for activating software.

Customizing your installation

By default, InventusTM

will be installed in the Program

Files directory on the drive that contains your

computer‟s operating system (typically the C drive):

C:\Windows\NovoInformatics\Inventus

If you wish to install Inventus in a different location

from the default path, select “Custom” during the

installation (Figure 1).


Figure 1. Customizing the Installation Location

Starting Inventus

A shortcut to Inventus will be included in your Start

menu, and a shortcut icon will be placed on your

desktop:

Start the Inventus application‟s graphical user interface

by one of the following methods:

Double-click the shortcut icon on your desktop

Select:

Start – Program files – Novo Informatics –

Inventus

AVINASH

Text Box

1. Go to installation folder, default is C:\Program Files\NovoInformatics\Inventus 2. Create a shortcut of DrugData application executable file. 3. Move the shortcut file to desktop. 4. Right click and rename it to Inventus. 5. This result in icon on desktop shown above.


Chapter 2

UNDERSTANDING INVENTUSTM

VISUAL INTERFACE

Figure 2. Inventus Virtual Interface

Interface Overview

Complete Interface of InventusTM

is divided into 3

panels. Left hand side screen displays predictive models,

Right hand side screen displays Tree (chains of proteins

along with residues numbers and atoms as well as

compound with atoms numbers); Middle panel displays

protein, protein-ligand complexes and ligand in different

visualizations. On top header, it has button tools for

performing operations such as uploading files, changing

visual formats, zoom in, zoom out, undo, redo, save

,save As, protein visualization window, ligand


visualization window, Contrast button. On the left hand

side screen, 4 tabs are displayed (Modules, Graphs,

PDB‟s & History).

Modules: Displays list of innovative

technologies for performing task on protein,

protein-ligand complex and ligand.

Graphs: User can utilize and design different

graphs for data. Pie chart, Bar chart and Line

chart for analyzing data

PDB’s: Tab will search out available PDB‟s on

your computer which you like to upload

History: User can check which task was run in

past. Complete history can be displayed.

Input file formats

InventusTM

supports two different types of input files:-

Protein-Ligand Complex/Protein – PDB

format

Ligand – SDF or PDB format (For small

molecules)

PharmoPredictaTM

Structure model format

files:

SMILES string

SD File

CSV File

TSV File

Note1: PDB is protein data bank file. Any

protein/protein-ligand complex file can be downloaded

from Protein Data Bank Database.

Note 2: SMILE string file is the default file type for

structural information.

Tabs Functioning FILE Tab

Options under File tab:-

Open (Protein/Protein-ligand complex files)

Format: PDB for protein & complex files and

SDF for compound files (Can be used to upload

folder for multiple compounds max. 15

compounds)


Opening protein/protein complex file

Opening ligand file

Inventus can extract multiple ligand at a time

(max 15) from folder saved on computer.


Figure 20. Displaying multiple ligand at a time.

SAVE AS

Options under SAVE AS tab:-

Picture

(PNG ,JPEG, BMP)

F

I

L

E


File

R

E

C

E

N

T

I

RECENT FLES

This tab helps users to open recently opened

protein files/protein-ligand complexes.


EXIT

This tab helps users to QUIT complete

application

.


VIEW TAB

Visual options under View tab:-

T

h

This tab helps user to visualize protein

file/protein-ligand complex file in different

visual formats

Upload protein/complex file using FILE tab

Click on view and multiple visual options will

open

Click on any visual option to see

protein/complex in different formats

Fig 3. Ball & Stick View

Fig 4. Ribbon View


Fig 5. Sphere View Fig 6. Wireframe View

Fig 7. Cartoon View

Fig 8. Tube View

Fig 9. Strand View Fig 10. Stick View


Tool Panel in View

Helps user to visual tool panel while visualizing

complexes in FULL SCREEN MODE

Fig 11. Using protein toolbox from toolbox under VIEW tab


Fig 12. Using Display Panel from toolbox under VIEW tab

Display Panel

Helps user to visualize

protein/ligands/protein-ligand complex

in different forms under FULL

SCREEN MODE. Also user can switch

off protein to visualize ligand and vice

versa.

TOOLS TAB

Information

This module gives the RCSB

information about the protein file, if

the files opened is in RCSB format.

And also gives Active Site

information about the opened

protein-ligand complex file.

R

CSB Information

OUTPUT


Active Site Information

Volume

Calculates volume of protein, ligand,

protein-ligand complex

Gives total volume, individual

volume and volume ratio.


R

R

Radius of Gyration

Calculates radius of gyration of

protein, ligand & protein-ligand

complex.

OUTPUT


Energy

Calculates Energy of protein target

OUTPUT


S

u

r

Surface Area

Calculates surface area of protein

target by selecting chain

S

i

d

e

Chain Donor Acceptors

OUTPUT Return to visualize mode

OUTPUT


Calculates side chain donor

acceptors of protein target

Secondary Structure

Calculates secondary structure

information of protein target.

S

u

p

OUTPUT


Superimpose

Superimpose chains/proteins over

other.

GEOMETRY TAB

Helps user to perform calculations on protein,

complexes for Dihedral angel, bond length,

centre of mass, centre of gravity.

Dihedral Angel

Tool to calculate angel between 4

atoms of protein target

OUTPUT


To calculate, click on PLAY button

on top tab panel

A

n

g

Angle

Tool to calculate angle between 3

atoms of protein target


on top tab panel

OUTPUT

PLAY


Bond Length

Tool to calculate bond length

between 2 atoms of protein target


on top tab panel.


Centre of Mass

Tool to calculate centre of mass for

complete protein structure

Result is displayed at the bottom

c

o

l

u

m

n

.

Centre of Gravity

Tool to calculate centre of gravity for

complete protein structure

Result is displayed at the bottom

C


Chapter 3

EnergyOptTM

- Module for optimizing

energy of protein target

(Modeled/Crystallized)

The protein structure optimizer minimizes the

energy of a protein target using combination of

steepest decent conjugate gradient minimization

algorithm using Cornell‟s force field equation.

Figure 13. EnergyOptTM

module

How to Run EnergyOptTM

Upload a pdb files in Inventus software

Click on EnergyOptTM

module

Select no of cycles to be run for steepest descent

and conjugate gradient (ex: 20 cycle each)

Select chain of protein file

Select type of minimization

Bonded Minimization

Non bonded minimization


Complete Minimization

Click on RUN Button

Note: Higher the number of cycles in steepest

descent and conjugate gradient, better will be the

optimization.

Output View

Once program is finished, Status will be updated

as DONE. If program is still in running mode,

status will be shown as RUNNING along with

colored progress bar.

Once program is finished, under RESULT Tab

click VIEW

A pop up window will open displaying result of

minimization (Figure )

Figure 14. Energy Minimization result for 2ADF


Chapter 4

MCSimulatorTM

- Module for Monte Carlo

Simulations

MCSimulator

TM is used to generate conformer using

three different methodologies

Perturbation of the terminal loop residue

Perturbation of any loop residue

Perturbation of any residue

Figure 15. MCSimulator

TM

How to Run MCSimulatorTM


Click on MCSimulatorTM

module

Select chain of protein target on which Monte

Carlo simulations to be run

Select number of steps

Select type of methodology

Perturbation of the terminal loop residue


Perturbation of any loop residue

Perturbation of any residue

Click on RUN Button

Note: Higher the number of cycles in steepest

descent and conjugate gradient, better will be the

optimization.

Output View






click VIEW



Figure 16. Monte Carlo Simulations for 2ADF


Chapter 5

PocketDetectorTM

- Module for discovering

active site in protein target

PocketDetector is a predictive tool of Inventus for

discovering active site in protein targets. Active sites are

given in ranking order and used as per user analysis

Figure 17. PocketDetector

TM

How to Run PocketDetector

TM


Click on PocketDetectorTM

module

Select pdb file of protein target

Select chain of protein target where active site is

to be detected

Click on RUN Button


Output View





Figure 18. PocketDetector

How to view active site

Click on pdb ID of protein target on which you

calculated active site

Selected distance from ligand molecule for

which you would like to view active site (option:

2Å, 5Å & 10Å)

Click on any cavity and SAVE text file of active

site

USER can view text file by uploading saved pdb

file of active site


Chapter 6

HitsGENTM

– Module for virtual high

throughput screening

HitsGen is a predictive tool of Inventus for undergoing

virtual high throughput screening.

Figure 19: HitsGen module on interface

Tabs in HitsGenTM

Molecules: Displays PDB‟s uploaded in

Inventus along with all the chains of each PDB

file selected.

Compound Libraries: Displays list of compound

libraries in Inventus

Generic – User can input customized

library of its own for running V-HTS on

selected protein active site


Target Specific Class: Selection of

compound library as per class of protein

target

Kinases

GPCR‟s

Ion Channels

Nucleases

Proteases

Disease Specific: Inventus is loaded

with selective compounds which have

been discovered against multiple

diseases and can be used for initial hits

for running computational studies

Alzheimer‟s

Cytomegalovirus

Hepatitis

Parkinson‟s

Diabetes

Huntington

Influenza

Properties: User can select multiple properties

for running HitsGen module. Each of these

properties plays an important role while

screening compounds for selective protein

target.

Weiner Index

Hydrogen Bond Acceptor

Hydrogen Bond Donor

LogP

Molar Refractivity

Functional Group

- Acid

- Alochal

- Sulphate/Phosphate

- Amide

- Aldehyde/Ketone

- Ester

- Amine

- Ether

No. of aromatic rings

Formal Charge

Length of Molecule

Total. No. of Atoms


Cut off Binding Energy

(Kcal/mol)

Figure 20. HitsGen run on 1AOE pdb file.

How to Run HitsGenTM

(In presence of

reference ligand)


Click on HitsGen module from module tab

Select pdb file; Select Chain; Select ligand

Select type of library to be used from Compound

Libraries selection window

Select different physico-chemical properties

Click on RUN Button

Output View






Once program is finished, click on View link

under RESULT Tab for viewing result of High

Throughput Screening.

Figure 21. Result of HitsGen on pdb ID: 1AOE

On clicking View button, result will be

displayed in different window as Figure 4.

Details of compounds will shown along with

their physico-chemical parameters against

selective active site of protein target.

All compounds can also be exported on excel

sheet.

To view compound in Inventus, USER can copy

SMILE string and convert it into PDB/SDF file

using public software. PDB/SDF file of

compounds can be uploaded in Inventus.

How to Run HitsGenTM

(In absence of

reference ligand)


Click on HitsGen module from module tab

Select pdb file; Select Chain; Select No ligand


Upload binding pocket file in asked browser (If

binding pocket is not available, use

PocketDetectorTM

and calculate active site

Select type of library to be used from Compound

Libraries selection window

Select different physico-chemical properties

Click on RUN Button

Figure 22. HitsGen on protein ID: 1AiL without having reference ligand attached

Output View






under RESULT Tab for viewing result of High

Throughput Screening.


Chapter 7

BioAffTM

Module for calculating binding

energy of protein-ligand complex

HitsGen is a predictive tool of Inventus for calculating

out binding energy of protein-ligand complexes.

Figure 23. BioAff module for calculating Binding energy of complexes.

For calculating binding energy of protein-ligand

complex, two different methodologies are used. User can

selected any methodology of them for calculating

energy.

AM1 BCC

Gasteiger

How to Run BioAffTM


Upload a pdb files in Inventus software from file

upload option

Click on BioAff module from module tab

Select pdb file; Select Chain and Select

Compound

Select type of methodology

Click on RUN Button

Figure 24. Running BioAff on protein ID: 1AOE using AM1 BCC methodology

Output View






under RESULT Tab for viewing result of BioAff

module.


Figure 25. Result of BioAff on 1AOE.

Once program is finished, Binding energy value

will be displayed under RESULT column and

status will show as DONE.

Result can also be exported to excel sheet by

clicking EXPORT button


Chapter 8

NovoDockerTM

Module for Docking studies

HitsGen is a tool of Inventus for undergoing

docking studies. Selection of protein target file

and compound is necessary

Figure 26. NovoDockerTM

How to Run NovoDockerTM


Click on NovoDockerTM

module

Select pdb file; Select Chain; Select NO ligand

Upload binding pocket site. If binding pocket

site is not available then calculate active site

using PocketDetectorTM

Upload Candidate ligand in Candidate Molecule

file name and path will be automatically selected

Click on RUN Button


Output View






CLICK and save Docking results on desktop .

Figure 27. Savings docking file on desktop

NovoDockerTM

will generate different

no. of docked poses and all be numbered

as per ascending order (eg: Rank 1 is

best docked pose).

Docked poses can be visualized in

Inventus under different mode of

visualizations for complex.


Chapter 9

ClashOptTM

- Module for removing steric

clashes in protein structures

ClashOptTM

module is used to remove steric

clashes in protein structures based on phi and psi

angles. This tool helps in optimizing protein

structure for Drug Discovery research

Figure 28. ClashOpt

TM

How to Run NovoDockerTM


Click on ClashOptTM

module

Select number of steps

Select chain of protein target on which Monte

Carlo simulations to be run

Click on RUN Button


Output View






click VIEW



Figure 29. ClashOpt for 2ADF Chain A.


Chapter 10

PharmoPredictaTM

Module for calculating

ADME properties of molecules

PharmoPredicta

TM is a comprehensive predictive ADME

software system developed and validated to predict

relevant pharmacokinetic and ADME characteristics of

potential drugs. pk ExpressTM

is bought from US based

company G2 Research Inc. The system can be deployed

as a PC desktop application or as an ADME compute

engine in a larger cheminformatics system. Inventus

pkEXPRESS includes the following:

• Physiological Absorption Model

• Physiological Metabolism Model

• Physiological Distribution and Elimination Model

Figure 30. Opening wizard of Inventus pkExpress

TM


How to Run PharmoPredictaTM

Click on PharmoPredictaTM

module

A new window of Inventus pkExpressTM

will

open in Inventus wizard

All operations for ADME will conducted on

Inventus pkExpressTM

wizard.

Note: A seprate manual designed by G2

Research Inc. for pkExpressTM

also included

with installation files.


Novo Informatics Pvt. Ltd.

Unit 303, Thapar House

Gulmohar Community Cemtre

Green Park, New Delhi- 110016

Contact: +91- 11- 46523123

Please contact for any discussion on USER GUIDE and

assistance for using software.

USER’s GUIDEscfbio-iitd.res.in/Setup_Inventus/USER_GUIDE- INVENTUS V1... · 2020-01-14 · 7...

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