integrated cadd methods - files.knime.com spring summit... · inflammation, cancer & immuno ......

Integrated CADD Methodsa Cocktail of KNIME, Bash and Modeling Software

Loris Moretti

KNIME Spring Summit 2018 Berlin, March 5-9, 2018

NUEVOLUTION COPYRIGHT & DISTRIBUTION RIGHT

TOPIC OF THE DAY

Outline

Nuevolution status and technology

The ligand-binding quest in Drug Discovery

Modeling infrastructure

HIV-1 protease as modeling example

Summary


Drug Discovery at Nuevolution


NUEVOLUTION A/S A Powerful Technology for Hit-Finding

Nuevolution A/S

Founded 2001

Located in central Copenhagen

37 employees in Science Department

Small molecule drug discovery

Chemetics® drug discovery platform

Internal and partnered programs

Inflammation, Cancer & Immuno-oncology

Listed on Nasdaq First North, Sweden, 2015 (uplisting soon)

...with global partnerships

...and global CRO support

http://www.google.dk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCPuinZC75MgCFUY-FAodDcQEQA&url=http://medicine.osu.edu/go/hhmi&psig=AFQjCNF08CY0gXZ36uRipwiCXiCrkEdYuA&ust=1446097459760052


THE CHEMETICS® LEAD DISCOVERY PLATFORM Fast and Efficient Generation, Selection and Identification of hits

~1 month ~2 days ~2 weeks

~60.000 Fragments

~5Libraries/Year

~500 Screenings/Year

~20 BTemplates/Year

DNA Encoded Library (DEL) Selection Identification

Re-synthesisConfirmationOptimization

Etc…


PURSUED TARGETSInternal Pipeline and Collaborations

We are active in the fields of INFLAMATION and ONCOLOGY (~25 targets)


EVERYDAY SCENARIO AT NUEVOLUTIONThe Ligand-Binding Players

NEEDLigand-binding hypothesis for ligand optimization

LIGAND

Small Molecules, 10s-1000s hits from CHEMETICS

TARGET

Many different proteins, receptors, enzymes, recognition

domain, etc…


The Ligand Binding Quest


knowledge

• Biological information

inputs

• Protein structure

• Ligand structure

modeling

• Docking software

outputs

• 1 or more poses

• Energy estimation

LIGAND-BINDING STUDYSelf Docking

Ligand-binding prediction

• LB known• RMSD• score


knowledge

• Biological information

inputs

• Protein structure

• Ligand structure

modeling

• Docking software

outputs

• 1 or more poses

• Energy estimation

LIGAND-BINDING STUDYCross Docking (Non-Native)


• LB known• van der Waals• Induced fit


LIGAND-BINDING STUDYA More Complex Picture: Drug Discovery Environment

knowledge

• literature information

• in house data

• activity data, biophysical, biochemical, In vitro, etc…

• Kd, Ki, IC50, EC50, etc…

• ADME/Tox data

inputs

Protein

• Xray (one or more), homology model

• binding sites, conformations, induce fit, plasticity

• role of waters, ionization, cofactor, ions, phys-chemproperties

Ligand

• chemotypes, flexibility, planarity,

• stereoisomers, tautomers, ionization

modeling

• protein preparation

• ligand preparation

• ligand exploration (QM)

• Software selection

• filters (pharmacophore)

• scoring

• Optimization (MM, MD)

outputs

• visualization

• prior knowledge

• 1 or more poses

• metrics for energy estimation

• ranking

• more binding modes


• LB unknown

MODELING HYPOTHESISdeal with these characteristics, issues, aspects…


LIGAND-BINDING STUDYWhen the Answer is Unknown

Expand and explore all the possibilities: protein states and ligands states

Consider more solutions: different hypotheses

Look for confirmation: prior knowledge, SAR, consistency

Unbiased view: different software and technology

Fraction into steps: more control over the process

Evaluate and explore each step: process tuning

…to be robust, reliable, automated, modifiable, traceable

COMPUTATIONAL INFRASTRUCTUREan environment to control and explore the modeling process


The Computational Infrastructure


COMPUTATIONAL INFRASTRUCTURESoftware Setup Concept

Moretti L., & Sartori L. (2016) Molecular informatics, 35(8-9), 382-390.Moretti L., & Sartori L. (2016) Molecular informatics, 35(10), 489-494.

Modeling software through

command line interface

Bash scripts wrapping modeling

software

KNIME Analytics platform protocols

for data flow and system calls


MODELING WORKFLOWInfrastructure in Layers: KNIME

Reads TXT input for files location and modeling parameters

Modeling steps interconnected through flow variables

Email with experiment specifications and results

Condition to run the step

SDF reader Actual modeling step

Handling of molecules files

Settings handling for the job

Process of the outputs

Command line for KNIME batch mode1

0

-1

-2

-3 System call to the modeling software (Bash)

from danish“LEg GOdt” (play well)


MODELING WORKFLOWInfrastructure in Layers: BASH

Main ScriptIntro and variables

Files and conditions

Modeling software execution and files transformation

Conclusion

Slurmqueuing management

Variables

Modeling task Script


COMPUTATIONAL INFRASTRUCTUREFeatures

Hardware and Software related

Servers with multiple CPUs and GPUs

Run in parallel

GNU/Linux Debian OS

Installation of third-party software (for modeling, analysis, etc.)

Python and Bash to glue together software and procedures (make a “flow”)

Process related

Nomenclature (identifiers) for targets, small-molecules and experiments

Environment variables customizable for target, small-molecules and experiments

File system structure for storing inputs and outputs, and for temporary files

Targets prepared in the same way (consistency)

Moretti L., & Sartori L. (2016) Molecular informatics, 35(8-9), 382-390.Moretti L., & Sartori L. (2016) Molecular informatics, 35(10), 489-494.


“MODELING BRICKS” AND PROTOCOLSEveryday Tasks

Knime Protocols

Docking

Scoring

Molecular Dynamics

Virtual Screening

Quantum Mechanics

Tasks and Software

Protein Preparation: Bash script with modeling software

Ligand Preparation: Ligprep, RDKit

Docking: Autodock, Vina, Plants, Glide, rDock

Poses Clustering: ACIAP1 and cut-off based

Molecular Mechanics: Ambertools and Gromacs

Scoring: plants, XScore, Drugscore, BEAR2, consensus score3,4

Interaction Fingerprint: Plants

Quantum Mechanics: Gamess-US

Reference Comparison: Python script

Binding Site Analysis: Voidoo, Fpocket, Caver

Favorable Interaction Regions: Autogrid, Autodock/Vina Pymol plugin5

Visualization: Pymol, Maestro, Jmol, Vmd, Bodil, Coot

Web interface: Django and Python 1Bottegoni G. et al., (2006) Bioinformatics, 22(14), e58-e65.2Degliesposti G. et al., (2011) Journal of biomolecular screening, 16(1), 129-133.3Charifson, P. S. et al., (1999) Journal of medicinal chemistry, 42(25), 5100-5109.4Oda, A. et al., (2006) Journal of chemical information and modeling, 46(1), 380-391.5Seeliger D., & de Groot B. L. (2010) Journal of computer-aided molecular design, 24(5), 417-422.


A Modeling Example


LIGAND-BINDING STUDYDocking Example

• Protein HIV-1 Protease• 11 ligands (15-23 rot bonds)• Complexes PDBs available• Cross docking on 1HXW


DOCKING EXAMPLESoftware and Sampling

AutodockGlide SPPlantsrDockVina

1 3

10 100

Poses X ligand X software

more poses and more programs


DOCKING EXAMPLEScoring

Post-optimization

PBSA:• optimization

Cscore: • optimization• Xscore +

DrugscoreX + Plants

• Customizable• Wider scope

AutodockGlide SPPlantsrDockVina

Combination of scoring metrics


DOCKING EXAMPLEClustering

Docking posesCluster best RmsdClusters medoidsClusters best cscore

• ACIAP implementation• Simplify conformational

space

Map and simplify the conformational space


DOCKING EXAMPLEPost-Docking Optimization

• MMFF94• Ligand minimization• Ambertools• Cscore• ”fast”

• BEAR• AM1-BCC• Complex min - Ligand MD – complex min• Ambertools• PBSA• ”slow”

Improve results with optimization


The Summary


SUMMARYIntegration for Robustness and Flexibility

A Drug Discovery environment: Nuevolution

“The Need” in a Drug Discovery environment: Ligand-Binding Assessment

Complexity: self, cross, real docking

Modeling infrastructure: …to be robust, reliable, automated, modifiable, traceable

Modeling infrastructure: Integration and customizable environment (LEGO)

KNIME + Bash + Third-party software

HIV-1 protease case: example of integration


THANKS

• Alex Haahr Gouliaev

• Thomas Franch

• Mads Nørregaard-Madsen

• Johannes Dolberg

• Aleksejs Kontijevskis

• All others at Nuevolution

• To the open-source and free software community

• To the KNIME team and community

…and you for the attention

NUEVOLUTION

TRANSFORMING CHALLENGESINTO MEDICINE

Visit us at:

https://nuevolution.com

Contact me at:

[email protected]

https://nuevolution.com/

integrated cadd methods - files.knime.com spring summit... · inflammation, cancer & immuno ......

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