Most Drug Discovery Scientists could be replaced by Software Systems

David E LeahyMolplex

Propositions

• Discovery Logistics “ a done deal”– Data and materials management processes built and running

• Discovery is Mature– established domains, established methodologies– best practice, strategies & success criteria– Operational, engineering & incremental change

• Discovery is a multi-objective optimisation– many genes, many (100’s) target, many drugs– Human understanding is a nice to have, not essential– Which compound do we make next?

• Discovery needs a Reboot– Simplify, abstract & re-implement

Facts and RulesPackage “Metabolic Clearance”rule “Last point outlier” when ObsVal.time(60) > FitVal.time(60) + 10thendelete ObsVal.time(6)refitend rule “another rule” whensomething == truethendo something elseend 0 10 20 30 40 50 60

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Facts, Events,Goals & PlansFact

Clearance(mol) = 50 ml/minEvent

add(mol)Goal

Clearance(mol) = ?Sub-goals

getClearance(mol)assayClearance(mol)predictClearance(mol)

Planssub-goal chains

Package “Clearance”

rule “Predict clearance if no measurement”Salience 10when

!getClearance(mol)then

predictClearance(mol)end

rule “Important compound”salience = 100when

important(mol)then

assayClearance(mol)end

findModels(clearance)

testApplicationDomain(mol)

allModelPredict(mol)

consensusAverage(mol)

addClearance(mol)

Sub-Goals and Plans(predictClearance)

Modelling Expert Strategies

Human Expert• Best Practice

– How

• Tacit Knowledge– When– Which

• Quality– Success criteria

Systems• Best Practice

– Workflows

• Tacit Knowledge– Rules (facts, events)– Competitive workflow

• Quality– Panel of experts

Competitive Workflow for QSAR

removeTest

•Random•ordered

selectSeries

•cluster•scaffold

calcDescriptors

•CDK•CDL•HState …

filterFeatures

•Stats•GA

buildModel

•Linear•NN

predict

•Ensemble•Weighted•best

QSAR Panel of Experts

Testing the Expert QSAR System

CHEMBL Database: data on 622,824 compounds,collected from 33,956 publications

WOMBAT-PK Database: data on 1230 compounds,for over 13,000 clinical measurements

WOMBAT Database: data on 251,560 structures,for over 1,966 targets

Project Junior (Newcastle University & Microsoft Research)

10,000 datasets gave 750,000 QSAR models in 3 weeks using 100 Azure Cloud Servers

From 750,000 QSAR models, 3,000 were judged stable and valid

QSAR Models

Panel of Experts

Events & Dashboards

Event

• Add(data)• Add(mol)• Add(reaction)• Add(reagent)• Add(goal)

Rule Set

• What strategy?

Workflow

• Goal chain• workflow• Competitive

workflow

Fact

• New facts• New events• New rules

Declarative Drug Design• Target Product Profile

– Panel of experts for a project– Set of rules– Sub-Target profiles (hit, lead,

candidate)• Goals

– Query – Assay– predict

• Engines– Forward chaining– Backward chaining– Workflow– Competitive workflow– Multi-Objective Optimisation

Package “TPP”rule “potency”when

potency(mol)==highthen

addLeads(mol)endrule “ good ADME”when

solubility(mol) > $minSol &&Papp(mol)> $minPapp && …

thenaddLeads(mol)

rule “no Tox”when

someToxEndPoint < someValthen

addLeads(mol)end

Multi-Property Optimisation Engines

Reboot