pka expert training and automation...training with pktraining with pka aaccuracaccuracy y extender...

21
pK a Expert Training and Automation Expert Training and Automation Eduard Kolovanov CSO, PhysChem and ADME/Tox

Upload: others

Post on 20-Jan-2020

10 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

pKaExpert Training and AutomationExpert Training and Automation

Eduard KolovanovCSO, PhysChem and ADME/Tox

Page 2: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Existing ways of ACD/pKa trainingExisting Methods for pKag y /p g

• ACD/Labs methods

TrainingACD/Labs methods• Compounds in User’s DB (Systematic Training)• pKa Accuracy Extender• pKa Accuracy Extender PROFESSIONAL

• PA method• Possible steps for AUTOMATION when using pKa AE

PRO

Page 3: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Systematic Training

Page 4: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Systematic TrainingSystematic Trainingy g

Advantages• Fast and simple to use• Fast and simple to use• One compound is enough to correct an entire

compound classDrawbacks

• No new Hammett equations. Only pK0 is corrected• Low accuracy

Page 5: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa Accuracy ExtenderTraining with pKa Accuracy g p y

Advantages

ExtenderAdvantages

• High accuracy is achieved• NEW Hammett Equations q

may be addedDrawbacks

NEW H tt E ti h ld b bt i d• NEW Hammett Equation should be obtained by user outside pKa AE

• Requires manual work outside pKa AERequires manual work outside pKa AE• Low performance because of previous

reasons

Page 6: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with ADME BOXESTraining with ADME SuitegAdvantages

• Automated• Easy to use • Calculation of RI

Drawbacks• “Black Box” for User

N H tt E ti• No Hammett Equations–correction for whole classes not very evidentnot very evident

Page 7: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO

Page 8: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PROTraining with pKa AE PRO g p

Advantages• NEW Hammett Equations may be added easily• NEW Hammett Equations may be added easily• High accuracy is achieved• High performance and speed of data utilizationHigh performance and speed of data utilization• ALL experimental information is used for training

without casual lossesDrawbacks

• Hard to use by non-expert users

Page 9: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

THREE Successful Examples of K AE PRO A li tipKa AE PRO Application

ACD/Labs Internal algorithm rebuilding• Fast speed—2 months for all Hammett equations

recalculation/improvement• Introducing multi substituted Reaction Centers• Introducing multi-substituted Reaction Centers

Work with GSK (2000 compounds, 1st experience)• 2 months for data preparation2 months for data preparation• 1 month for data analysis

Work with UCB Celltech (2000 compounds, 2nd experience)• 1 month for data preparation• 1 week for data analysis (on-site visit)

Page 10: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Results of ACD/Labs Internal Algorithm Rebuilding (InternalAlgorithm Rebuilding (Internal

Dataset)ClassName Sceleton Count Subst Count

ver. 12 ver. 10 ver. 12 ver. 10

alpha‐amino acids and derivatives 50 16 102 22

C id 26 2 3 29CH‐acids 26 21 37 29

all primary amines 87 61 151 108

secondary amines 87 26 167 40

t ti i 26 20 28 20tertiary amines 26 20 28 20

Imidazoles 12 5 38 15

Piperazines 12 3 29 5

Piperidines 14 1 31 1Piperidines 14 1 31 1

Pyrazines 4 2 11 3

Pyrimidines 46 11 105 18

Quinolines 23 5 49 13Quinolines 23 5 49 13

6‐member heteroaromatics 194 45 456 97

TOTAL in DB 1024 591 2009 1050

Page 11: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Results of ACD/Labs Internal Algorithm Rebuilding (InternalAlgorithm Rebuilding (Internal

Dataset)N R2 MAE

BEFORE algorithm rebuilding,  11,972 0.955 0.491g g,version 10

,

AFTER algorithm rebuilding,i

12,095 0.965 0.416version 12

Page 12: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Results of ACD/Labs Internal Algorithm Rebuilding (External

D t t f 655 K l f “I Sili P di ti f

Algorithm Rebuilding (External Dataset)

Data set of 655 pKa values from “In Silico Prediction of Physicochemical Properties (Report for European Commission, 2007)” by John Dearden and Andrew Worth, ) y

R2 MAE

BEFORE algorithm rebuilding, version 8 0.68 1.07

AFTER algorithm rebuilding, versions  12 0.92 0.54

Page 13: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Results of Expert training with GSK d UCB C llt hGSK and UCB Celltech

Statistics is presented for same ~4000 compounds whereStatistics is presented for same 4000 compounds, where some were used for training file calculations.

Feedback from GSK and UCB was that new compounds

R2 MAE

were also much improved.

R MAE

BEFORE Training ~ 0.7 ~ 1.0

AFTER Training 0 9 0 5AFTER Training ~ 0.9 ~ 0.5

Page 14: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO Workflow

AutomatedAutomated• Generation of ALL perspective Reaction Centers (Step

#2))

Semi-Automated• pKa Assignment (Step #1)

N t A t t dNot Automated• Hammett Equation Calculation (Step #3)

Page 15: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO• Step 1 – pKa Assignment• Auto pK assignment with ACD/Labs pK algorithm• Auto pKa assignment with ACD/Labs pKa algorithm• Auto pKa assignment with PA pKa algorithm• Manual checking (visually or by “double” assignment)Manual checking (visually or by double assignment)

• How to make assignment FULLY automatic?• It is possible to create combined auto-assignment

procedure with 1 or 2 assignments of same pKavaluevalue.

Page 16: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO Step 2—Generation of ALL perspective Reaction Centers

Page 17: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO Step 3—Analysis, Equations Calculation

Page 18: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO Challenges for full Automation

Calculation of Accurate Hammett Equation:• Selection of appropriate Sigma constants

R i i t l l d tli• Removing wrong experimental values and outliers• Reasonable detailing of Reaction Centers:

NH+N

R2

NH+N

R2

NH+N

R2

HNH+N

F

HR3 R1 NH2 R1 N

H

HR1 N

H

HR1

Page 19: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO Challenges for full Automation

• Additional Problems:• Addition of Hammett Equation when it can not be

calculated by software or statistically insignificant (Expert may force the program to use the Equation)

• After successful training of some pK (micro) when• After successful training of some pKa (micro), when calculate apparent pKa, another micro-pKa appears as most important and determines an apparent pKa—dditi l t i i i i dadditional training is required

Page 20: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Training with pKa AE PRO Challenges for full Automation

Form mostly depending on

NNH +

FF

Form mostly depending onapparent pKa BEFORE Training Form mostly depending on

apparent pKa AFTER Training

NH+N

NH N

FNNH

NH2 NNN

NH2 N+

NH2 N

+

R2R2

First Training stepSecond (additional)

2‐fluoro‐N,N‐dimethylpyrimidine‐4,6‐diamine

NH+N

NH

HR1

NNH+

R3

2

NR

R

( )Training step

R

Page 21: pKa Expert Training and Automation...Training with pKTraining with pKa aAccuracAccuracy y Extender Advantages Extende r • High accuracy is achieved • NEW Hammett Equations may

Questions

• Is anyone interested in on-site development of pKa user training files?

• Is anyone interested in development of MORE Automated pKa EXPERT user training?u o a ed p a use a g

• Your questions…