Large scale virtual molecular docking now in reach for a wider

biochemical community

BOINC, AutoDock and Debianwiki.debian.org/BOINC/ServerGuide

Dhananjay BalanTomas Malinauskas

Pjotr PrinsSteffen Möller

Should there be more initiatives to search for new drugs and drug targets?

Who has the skills?

Who has the resources?

Drug screening

● Identified drug target● Compound “library” to test● Cellular assay

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Virtual drug screening

● Protein structure of drug target● Compound formula list● Docking application (AutoDock. BALLView, ..)

Considerablebiochemical insightsrequired.

Field of application

● Many rare (→ neglected) diseases– Regional (e.g., local parasites)

– Social subcommunities (e.g., eldery, poor, sexual orientation …)

– Just rare, or too slowly progressing to find awareness

● Many more individuals → many cases● Difficult to predict

– Many diseases share genetic defects

– Common cross-application of functional compounds

Motivation

● Many high throughput technologies identifying interesting drug targets– System Genetics (SNPs, expression data)

– Multiple efforts towards rare diseases

● Steady improvements on structural resources– “Strukturfabrik”

– Higher resolutions of higher fruits

– Homology modeling

● Gap between those who know and those who could– IT in biochemistry is (too often) weak

– The converse even weaker

– Little motivation / no proof without (pre-)clinical background

Communication

Technology

Challenge● Lower hurdles

– Provide experiment templates

– Provide application binaries

– Provide drug-like ligand data

– Provide compute infrastructure

● Ease pain– Reduce setup time

– Reduce compute time

– Reduce costs

● Strengthen communication● Education

Enormous demands.

Reduces uncertaintiesand speeds up process.

Approach

Provide complete toolset, data and instructions through Debian/Ubuntu Linux– MGLTools : preparation of experimental setup

● AutoDockToolkit – specification of constraints● Raccoon – preparation of screening data

– AutoDock : program for molecular docking

– BOINC : distributed data parallel computation– Debian

● Packages: immediate availability● Cross-platform● Wiki : instructions

Setup● BOINC – typical, to be performed by CS student

– Server pages

– Wrapper of command line tool for every platform

– AutoDock for every platform

● Docking – typical, to be perform by skilled biochemist– Identification of binding site, characterisation (e.g. flexible residues)– Selection and preparation of ligand database

● Server Infrastructure – typical– Local machine

– Cloud as alternative

● Client Infrastructure– Volunteers' desktops– Cloud or compute cluster to complement

Setup

BOINCServer

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

Many independent machines running the BOINC client.

Setup

BOINCServer

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

BOINCClient

Provided with compute jobs and binaries by project server

Database onligand-receptor

affinities

Liganddatabase

AutoDock forMac, PC, Linux

Client side

Shipping with Debian, or downloadable from BOINC developers

Executing wrapper application, which executes autodock and communicates output back to core client.

AutoDock

Communication with BOINC Project Server

BOINC documentation

Installation

BOINC documentation

Debian renders the software immediately available

Configuration

Complete analogy to regular BOINC instructions, official paths

Preparation of scientific Application

● Debian provides for all common Linux platforms– the AutoDock binary

– the Wrapper tool

● The Debian Wiki provides templates and instructions for the preparation of– the Wrapper

– Jobs descriptions for the boinc server

Where is the parallelism?

● Volunteer computing – data parallelism● Biological research

– More biochemical groups get computationally ready for in silico screening

– Expecting exchange of recipes for docking

– More biomedical investigations performed in parallel

Summary / Outlook

● We are the first – not about describing BOINC-based docking

– but to provide a free template for everyone to use

– and for increasing the parallelism wrt targets and compute resources employed

● Instructions are seen– Discussed in the BOINC community

– Need biochemical publication to attract audience of biochemists

● We are now the first ourselves to perform a real project this technology– Highly speculative

– Educational

– All run from within the Department of Dermatology

● Community education by Open Source principles– Heterogeneous projects demand heterogeneous skills

– Cross-institutional funding is scarce

– Software developers and package providers as consultants

Acknowledgements● Molecular Graphics Lab @ Scripps

– M. Garrett, S. Dallakyan, S. Forli, R. Huey and colleagues developing AutoDock (autodock.scripps.edu) and MGLTools (mgltools.scripps.edu)

– Kindly helping with questions and reviewing the manuscript.

● BOINC community– David Anderson, Rom Walton (BOINC Developers)

– Carsten Aulbert, Oliver Bock (Hannover)

– Everyone contributing to Docking@Home, FightAids@Home

● Debian community is supportive● Google for their Summer of Code● Our employers for supporting such side projects

– University of Lübeck, Germany

– University of Oxford, UK

– University of Wageningen, The Netherlands

– College Of Engineering Trivandrum, India