(ATS4-PLAT04) Chemistry Data Model Enhancements in Pipeline Pilot 9.0: what are they and how will they impact your users

(ATS4-PLAT04) Chemistry Data Model Enhancements in Pipeline Pilot 9.0: what are they and how will they impact your users

Keith T Taylor PhD

Advisory Product Manager, Chemistry Foundation

[email protected]

The information on the roadmap and future software development efforts are intended to outline general product direction and should not be relied on in making a purchasing decision.

• Enhanced representation – What you see is what you have

• New representations – New mapping options – Streamlined mapping

• Consistency between Pipeline Pilot Chemistry, Accelrys Direct, and Accelrys Draw

• Changes to perception mean that models, and calculators must be relearned and re-baselined – Significant effect from new ring perception option – Stereochemistry and aromaticity have smaller, but important effect

Pipeline Pilot 9.0 – New Capabilities

• Pipeline Pilot 9.0 (2013) will support all chemical representations supported by Direct and Draw – Generics – Biologics – Polymers and Mixtures – Variable attachments – Homology Groups – Haptic Structures – New bond types

• Depiction of all chemical objects supported by Accelrys Direct and Accelrys Draw – Look and feel that matches those of Accelrys Draw

• Mappers upgraded to support new representations

• Calculators upgraded to interpret the new representations appropriately

• Enhanced perceptions of stereochemistry. aromaticity, and rings

Pipeline Pilot 9.0 – New Capabilities

• Single/double/triple bonds supported in NONS

• Coordination/Dative bond

• Haptic bonds

• Markush Homology Groups

• Hydrogen bonds

Chemical Representations – New in 9.0

• Rendering between Accelrys Draw and Pipeline Pilot 9.0 now consistent

• Pipeline Pilot now supports: – PNG – JPEG – GIF – SVG – EMF – Linux and Windows!

• SVG and EMF generation fast – ~ 10,000 structures per second

Depiction

Draw

Pipeline Pilot

• Abbreviated groups are frequently used to simplify structures

• Attachment points are now correct – The Pipeline Pilot 8.x depictions are incorrect on the left of the phenyl

group

– The labels depicted imply different chemical entities

• Visual corruption

• Nitrile (CN) and isonitrile (NC) are chemically different

• NCS and SCN are also different entities

• Rich text markup renders correctly

• Whitespace around labels is consistent – Affects perceived bond length

Abbreviated groups render correctly

Draw

Pipeline Pilot

• Markush/Rgroup depiction is complete in Pipeline Pilot rendering

• Now renders – Rgroups definitions (e.g. R1 …)

– Rgroup logic (R1 = 1; R2 >= 0)

– Indication of direction for fragments with multiple attachment points (e.g. “ on R2)

Rgroup/Markush is functional

Draw

Pipeline Pilot

• Nonspecific (NONS) representation are equivalent with Direct 8.0 and Draw 4.1

– Pipeline Pilot version does not lose information

• Examples from mass spectrometry and industrial chemicals

Nonspecific representations are rendered

Draw

Draw

Pipeline Pilot

Pipeline Pilot

• Growing importance

• Representation exposed in Pipeline Pilot 8.5

• Completed in 9.0

– Much more functional and sophisticated

Biologics

Pipeline Pilot

Draw

• Representation and search new in 9.0

• Mix it up

Polymers, Mixtures, and Formulations New in 9.0

• Accelrys Direct and Accelrys Draw understand Antibody-Drug Conjugates

Example: Antibody-Drug Conjugates – New in 9.0

• Pipeline Pilot 9 understands Antibody-Drug Conjugates (ADC) – And with variable loading

• Harmonization facilitates support of all of Accelrys’ chemical representation in applications – Antibody-drug conjugates, polymers, formulation, mixtures, and metabolites

• Benefits of harmonized chemical representation are:

– Implement once

– Expose everywhere

– Consistent

Example: Antibody-Drug Conjugates

What does this mean to my scientists? (1)

• Higher quality reports

– Supports perception of quality research

• Enhanced depiction of biologics and Markush generics

– Will look different and minor adjustments to depiction protocols may be needed

• New chemical representations

– No change to existing protocols

– New opportunities open up

• Enhanced mapping – New in 9.0 e.g. Imipramine Metabolites

Mapping: Non Specific Structures - New

• Screen MDDR data set – 129,237 structures screened in ~30s

– No pre-processing

Mapping: Homology group screening

Hits = 470

Hits = 108

Hits = 45

Hits = 16

Hits = 10

What does this mean to my scientists? (2)

• New mapping capabilities – No change to existing protocols

– Enhancements to existing protocols – more efficient code

– New screening opportunities – screen by homology

• Changes to stereochemical and aromaticity perception will drive changes in the behavior of:

– Learned models

– Calculators

– Structure Matchers

• Will need to relearned and re-baselined

• Change is discontinuous

• There will be no legacy mode

– Because this will cause incompatibilities and drive confusion

Data Model Changes from PP 8.x PP9

• Pipeline Pilot 9.0 (2012) and Accelrys Direct 9.0 (2013) – Will be 100% compatible

• Pipeline Pilot 9.0 and Accelrys Direct 8.0 – Only difference is aromaticity perception edge-cases

– Direct 8.0 will use its current aromaticity perception

• Template based

– Will differ from that in Pipeline Pilot 9.0

• Hückel (4n+2) rule based

– Minor differences will be observed

Compatibility: Pipeline Pilot and Accelrys Direct

Dataset Number of Structures

Canonical SMILES

AlogP Number of

Rings Number of

Aromatic Rings Number of

Stereo Atoms ECFP4

ACD 239,996 251 105 2,455 65 0 214

Asinex 137,799 26 24 1,070 22 0 43

Maybridge 51,058 2 0 438 0 0 1

MDDR 2010 201,748 62 24 3,271 29 4 46

WDI 53,517 37 14 612 10 0 42

Observed Differences in Calculated Values

• Table shows the number of structures in the datasets that had different values in 9.0 compared with 8.5

• Difference generally very small

• Ring perception leads to more prominent differences especially in drug-like datasets

• Single chemistry foundation with single data model implemented in

a single code stream

– Adopted by Tools and Platform

• Direct , Pipeline Pilot and Accelrys Enterprise Platform

– Application Stack inherits all of the chemistry capabilities

• Simplifies development and application environment

• Enhances our ability to deliver to you new functionality more quickly across the products

Harmonization delivers

• Chemistry Harmonization project: – PPChem 9.0 inherits many new chemical representations – Existing representations enhanced – Aromaticity, Stereochemistry and Ring perceptions enhanced – Significant improvement to depiction aesthetics – PPChem 9.0 and Direct 8.0 share representations(1)

• Pipeline Pilot 9 and Direct 9 deliver the same results

• What Next – Get early access by joining the beta2 program – Get feedback from your chemists – What opportunities do the new features open up?

• Related Tech Summit Sessions (Current or previous)]

Summary

Chemistry Data Model

Changes to Chemical Perception Details

• Charged non-metals are now treated as their “isoelectronic” equivalent: – B- ~ C ~ N+ ~ O+2 ~ F+3

– Si- ~ P ~ S+ ~ Cl+2

• The bad valence filter has been improved and now catches more bad anions.

• Metal anions no longer have implicit hydrogens – Aluminum anions are an exception (for support of aluminum hydride anion)

• Nitrogen (V) is still allowed as a drawing alternative for nitro- and diazo- groups, amine oxides, and related substructures. However, the application is now less likely to perceive uncharged quaternary nitrogens as implicit hydrogens.

• Atoms with illegal valence are now better distinguished from atoms with maximum valence in ECFP fingerprint bits. For example, the Oxygen in N=O and N#O is now typed differently. This can affect the Canonical SMILES atom order for structures containing atoms with illegal valence.

• The changes in valence result in changes to ECFP fingerprint bits and Canonical SMILES.

Valence and Implicit Hydrogens

• Ring perception has been improved. Previously, the SSSR ring perception algorithm was used, which is not unique and often misses rings in complex non-planar assemblies, when they were atom-order and bond-order dependent. The unique “K-rings” perception algorithm is now used, which is the union of all possible SSSR sets. These changes result in changes to Canonical SMILES and improvement to aromaticity perception.

• Examples

• Now perceived as 3 rings:

• Now perceived as 4 rings:

• Now perceived as 6 rings:

Rings

• The isoelectronic equivalence enhancement described in Valence and Implicit Hydrogens improves the perception of ring systems containing charged non-metals. Improved detection of bad valence for anions also contributes to improved perception of aromaticity.

• The atoms that can contribute a lone pair to an aromatic ring are extended from (N,O,P,S) to include As, Se, and Te.

• These changes result in changes to ECFP fingerprint bits and Canonical SMILES.

Examples

• Now perceived as aromatic:

• No longer perceived as aromatic:

Aromaticity Perception

• The isoelectronic equivalence enhancement described in Valence and Implicit Hydrogens improves the perception of stereogenic centers that include charged non-metals.

• The symmetric equivalence of O-/OH/=O groups attached to P and S atoms has been extended to include As, Se, and Te centers.

• Stereo validation logic of reader code is synchronized with perception code. This allows for more consistent application of rules prohibiting S(IV) centers, P(V) centers, symmetric equivalence of O-/OH/=O, etc.

• “Double-symmetric” ring atom perception is improved Several symmetric spiro cases are now correctly not marked as pseudo-stereo.

Examples

• Now perceived as stereo:

•

• More consistently perceived as not stereo:

•

• No longer perceived as pseudostereo:

Stereochemical Perception