Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

CINF 17: Comparing Cahn-Ingold-Prelog Rule Implementations: The need for an open cip

1,084 views

Published on

The Cahn-Ingold-Prelog (CIP) priority rules have been the corner stone in written communication of stereo-chemical configuration for more than half a century. The rules rank ligands around a stereocentre allowing an atom order and layout invariant stereo-descriptor to be assigned, for example R (right) or S (left) for tetrahedral atoms. Despite their widespread daily use, many chemists may be surprised to find that beyond trivial cases, different software may assign different labels to the same structure diagram.

There have been several attempts to either replace or amend the CIP rules. This talk will highlight the more challenging aspects of the ranking and present a comparison of software that provide CIP labels and where they disagree. Providing an IUPAC verified free and open source CIP implementation would allow software maintainers and vendors to validate and improve their implementations. Ultimately this would improve the accuracy in exchange of written chemical information for all.

Published in: Science
  • Be the first to comment

CINF 17: Comparing Cahn-Ingold-Prelog Rule Implementations: The need for an open cip

  1. 1. ACS Fall 2017, Washington, D.C. comparing cahn-ingold-prelog rule implementations: the need for an open cip John Mayfield, Daniel Lowe, Roger Sayle
  2. 2. “The Cahn–Ingold–Prelog (CIP) sequence rules … are a standard process used in organic chemistry to completely and unequivocally name a stereoisomer of a molecule.” - Wikipedia
  3. 3. “The Cahn–Ingold–Prelog (CIP) sequence rules … are a standard process used in organic chemistry to completely and unequivocally name a stereoisomer of a molecule.” - Wikipedia If you are not naming stereoisomers you (probably) don’t want to use CIP Tools can give different answers, What can we do about it?
  4. 4. NUMBER OF STEREOCENTRES PER ENTRY 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 % of Dataset Count 0 1 2 3 4 5 6 7 8 9 eMolecules 2017-Jun-01 PubChem Substance PubChem Compound (Aug 17) ChEMBL 23 ChEBI 154 + 14 million total 234 million total 93 million total 1.7 million total 95 thousand total
  5. 5. Many chemists are taught the CIP rules during their education and is deceptively simple ‣ Simple cases are easy for a human (and computers) ‣ Complex cases are hard for a human (and computers) IUPAC Blue Book (2013) extends recommendations but incomplete (and some mistakes)
  6. 6. The Sequence RULES (in essence) Rule 1 a. Higher atomic number precedes lower b. An atom node duplicated closer to the root ranks higher than one duplicated further Rule 2 Higher atomic mass number precedes lower Rule 3 Z precedes E and this precedes nonstereogenic (nst) double bonds Rule 4 a. Chiral stereogenic units precede pseudoasymmetric stereogenic units and these precede nonstereogenic units (R = S > r = s > nst) b. When two ligands have different descriptor pairs, the one with the first chosen like descriptor pairs has priority over the one with a corresponding unlike descriptor pairs c. r precedes s Rule 5 An atom or group with descriptor R has priority over its enantiomorph S
  7. 7. O H H H H H H H H H 321 5 4 6 1 2 3 5 6 4 H Example 1. In the sphere (i) C2 and C5 are tied O > C5 = C2 > H 2. In the sphere (ii) C2 and C5 are split C,H,H > H,H,H and therefore C2 > C5 3. The priority is 4, 2, 5, 6 and the configuration is S (i) (ii)
  8. 8. DIGRAPHS • Rules are applied to hierarchal directed acyclic graphs (digraphs) • Comparison proceeds in “spheres” out from the root of the graph • Combinatorial explosions for some structures H OH H H H H H H H H H 1 7 6 5 (1) (1) 65234 O O 3 4 2 1 6 5 7 7
  9. 9. PSEUDO-ASYMMETRY Some confusion of lower case r and s • Assigned only when Rule 5 has been used • Not indication of non-constitutional Why? Reflection is superimposable:
  10. 10. AUXILIARY DESCRIPTORS Auxiliary descriptors are used to split ties by symmetric molecules by labelling the asymmetric digraphs Tie in initial digraph Calculate auxiliary descriptors R > S (Rule 5) 3:r Picture: May, J. W. (2015). Cheminformatics for genome-scale metabolic reconstructions (doctoral thesis).
  11. 11. mancude ring handling P-92.1.4.4 Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 Kekulé forms can result if different digraphs Handled using fractional atomic numbers
  12. 12. The Sequence RULES (in essence) Rule 1 a. Higher atomic number precedes lower b. An atom node duplicated closer to the root ranks higher than one duplicated further Rule 2 Higher atomic mass number precedes lower Rule 3 Z precedes E and this precedes nonstereogenic (nst) double bonds Rule 4 a. Chiral stereogenic units precede pseudoasymmetric stereogenic units and these precede nonstereogenic units (R = S > r = s > nst) b. When two ligands have different descriptor pairs, the one with the first chosen like descriptor pairs has priority over the one with a corresponding unlike descriptor pairs c. r precedes s Rule 5 An atom or group with descriptor R has priority over its enantiomorph S
  13. 13. ChEBI ChEMBL eMolecules PubChem Compound PubChem Substance Rule 1a 281K 99.6% 1.8M 98.6% 2.4M 97.0% 53.5M 100.0% 93.1M 98.7% Rule 1b 4 1 164 255 Rule 2 14 3,565 6,789 Rule 3 29 3 441 36 45 Rule 4a 122 126 273 4 12,770 Rule 4b 563 0.2% 4,037 0.2% 3,188 0.1% 125K 0.1% Rule 4c 19 558 Rule 5 285 0.1% 23.4K 1.2% 69K 2.8% 15 1.1M 1.2% Total 282K 1.9M 2.4M 53.5M 94.3M MAJORITY HANDLED BY RULE 1a Count is number of stereocentres, values of zero and percentages close to zero removed to reduce complexity
  14. 14. 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 1 2 3 4 5 6 7 8 9 10 Sphere %ofStereocentres Dataset chebi_154 chembl_23 eMolecules170601 pubchem pubchem_substance distance from root Majority (but not all) stereocentres labelled within first few spheres Best to generate digraph lazily as required Some digraphs are far too big to generate fully (e.g. fullerenes) 5 6 7 8 9 10 phere Dataset chebi_154 chembl_23 eMolecules170601 pubchem pubchem_substance
  15. 15. comparison
  16. 16. Rule 1A I II Centres 2.0 R R JMol 14.20.3 R R ACD/ChemSketch 14.05beta R R Balloon 1.6.5beta R R KnowItAll ChemWindow 2018 R R ChemDraw 16.0 R R BIOVIA Draw 2017 R R MarvinSketch 17.17 R - Indigo 1.3.0Beta.r16 - R RDKit 2017.03.03 S R DataWarrior 4.6.0 R R CACTVS (NCI Resolver Aug 17) R R OPSIN 2.3.1 R R LexiChem (OEChem) 20170613 R R ChemDoodle 7.0.2 R R CDK 2.0 - R JUMBO 6 R - I II
  17. 17. Rule 1B Centres 2.0 R JMol 14.20.3 R ACD/ChemSketch 14.05beta R Balloon 1.6.5beta R KnowItAll ChemWindow 2018 R ChemDraw 16.0 R BIOVIA Draw 2017 - MarvinSketch 17.17 - Indigo 1.3.0Beta.r16 - RDKit 2017.03.03 R DataWarrior 4.6.0 - CACTVS (NCI Resolver Aug 17) - OPSIN 2.3.1 R LexiChem (OEChem) 20170613 - ChemDoodle 7.0.2 - CDK 2.0 - JUMBO 6 -
  18. 18. Rule 2 Jan 2015 Aug 2017 Centres R R JMol n/a R ACD/ChemSketch R R Balloon 1.6.5beta n/a R KnowItAll ChemWindow n/a R ChemDraw S S Accelrys/BIOVIA Draw S R MarvinSketch S S Indigo R R RDKit S S DataWarrior S S CACTVS S R OPSIN R R LexiChem (OEChem) S R ChemDoodle S n/a CDK S S JUMBO - - R or S? Let’s Vote https://nextmovesoftware.com/blog/2015/01/21/r-or-s-lets-vote/
  19. 19. Rule 4b S S S R Centres 2.0 R JMol 14.20.3 R ACD/ChemSketch 14.05beta R Balloon 1.6.5beta R KnowItAll ChemWindow 2018 R ChemDraw 16.0 R BIOVIA Draw 2017 R MarvinSketch 17.17 R Indigo 1.3.0Beta.r16 R RDKit 2017.03.03 S DataWarrior 4.6.0 S CACTVS (NCI Resolver Aug 17) S OPSIN 2.3.1 - LexiChem (OEChem) 20170613 - ChemDoodle 7.0.2 s CDK 2.0 - JUMBO 6 -
  20. 20. MANCUDE RINGS Centres 2.0 R R JMol 14.20.3 R R ACD/ChemSketch 14.05beta R R Balloon 1.6.5beta R R KnowItAll ChemWindow 2018 R R ChemDraw 16.0 R R BIOVIA Draw 2017 R R MarvinSketch 17.17 R R Indigo 1.3.0Beta.r16 S R RDKit 2017.03.03 R R DataWarrior 4.6.0 R R CACTVS (NCI Resolver Aug 17) S R OPSIN 2.3.1 S R LexiChem (OEChem) 20170613 S R ChemDoodle 7.0.2 S R CDK 2.0 S R JUMBO 6 S S I II I II
  21. 21. Centres 2.0 R JMol 14.20.3 R ACD/ChemSketch 14.05beta R Balloon 1.6.5beta R KnowItAll ChemWindow 2018 R ChemDraw 16.0 R BIOVIA Draw 2017 R MarvinSketch 17.17 - Indigo 1.3.0Beta.r16 - RDKit 2017.03.03 - DataWarrior 4.6.0 - CACTVS (NCI Resolver Aug 17) - OPSIN 2.3.1 - LexiChem (OEChem) 20170613 - ChemDoodle 7.0.2 - CDK 2.0 - JUMBO 6 - AUX DESCRIPTORS
  22. 22. hard to implement A MarvinSketch 17.17 (S) O O (S) OH (S) O O (R) OH Turning aromaticity on flips stereochemistry (e.g. CHEBI:16063) Labels depend on input order OH 1 (S)2 (r) 3 OH 4 (R) 5 OH 6 (S)7 OH 8 (s)9 HO 1 0 (R) 1 1 HO 1 2 (S)1 OH 2 OH 3 (R) 4 HO 5 OH 6 (R) 7 OH 8 (S)9 (R) 1 0 (R) 1 1 HO 1 2 (r) 1 OH 2 (s)3 HO 4 (S)5 (R) 6 (S) 7 (R)8 OH 9 OH1 0 HO 1 1 OH 1 2
  23. 23. hard to implement B (R) OH H (CH2)2CH2HO OH (R) OH H (CH2)11(CH2)10HO OH OH H (CH2)17(CH2)16HO OH Becomes undefined distance ≥ 16 ChemDraw 16.0 (R) (s) (CH2)2 (R) OH (r) (s) (CH2)11 (R) OH
  24. 24. open cip? Why? • Provide a blessed implementation that can be used directly or compared against • Toolkit agnostic library to facilitate downstream integration
  25. 25. “FIX-CIP” CoLABORATION Robert Hanson (JMol), John Mayfield (Centres) Mikko Vainio (Balloon), Andrey Yerin (ACD/Name), Sophia Gillian Musacchio (St. Olaf College) Goals • Discuss and resolve software inconsistencies • Generate comprehensive test set based on BlueBook structure • Recomend rule amendments and additions Publication in preparation
  26. 26. should you use CIP? Yes Systematic nomenclature Human conversation (if no pen is handy) Probably not (better algorithms exist) Unique labelling (see right) Compute “conversation” Finding/cleaning stereocentres No Relative comparison, e.g. substructure search
  27. 27. should you use CIP? Yes Systematic nomenclature Human conversation (if no pen is handy) Probably not (better algorithms exist) Unique labelling (see right) Compute “conversation” Finding/cleaning stereocentres No Relative comparison, e.g. substructure search (S) (S) (R) (S) (R) (R) (S)(R) (S) (S) (R) (S) (R) (R) (S)(R)
  28. 28. acknowledgements SciMix Poster Robert Hanson (JMol) Mikko Vainio (Balloon) Andrey Yerin (ACD/Name) Sophia Gillian Musacchio (St. Olaf College) Karl Nedwed (Bio-Rad) Noel O’Boyle (NextMove Software) Shuzhe Wang (NextMove Software) John Mayfield, Daniel Lowe and Roger Sayle NextMove Software Ltd, Cambridge, UK. NextMove Software Limited Innovation Centre (Unit 23) Cambridge Science Park Milton Road, Cambridge UK CB4 0EY www.nextmovesoftware.com Introduction Robert Hanson, Andrey Yerin, Mikko Vainio, and Sophia Gillian Musacchio for initiating and participating in the “Fix CIP” collaboration and the many in-depth technical discussions that have lead to improvements in the tools. Karl Nedwed for providing KnowItAll results. Philip Skinner for providing ChemDraw licenses. Noel O’Boyle for feedback and suggestions. the need for open-cip The Cahn-Ingold-Prelog (CIP) priority rules rank atoms around a stereogenic unit to assign a stereo-descriptor that is invariant to atom order and layout, for example R (right) or S (left) for tetrahedral atoms. A directed acyclic graph (digraph) is constructed for each stereogenic unit and the out edges from the root node compared and ranked according to eight sequence rules[1]. Each rule is applied exhaustively and tested on the entire digraph before applying the next rule[2]. Acknowledgements Results 1. P-92.1.3 Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 2. Paulina Mata. The CIP System Again:  Respecting Hierarchies Is Always a Must. J. Chem. Inf. Comput. Sci., 1999, 39 (6) Bibliography Conclusion The CIP sequence rules provide a standard way for chemists to effectively describe the configurations of most stereogenic units. However, beyond simple cases the complexity of the rules necessitates software is used as an aid to naming configurations. The results demonstrate even then, software implementations do not all agree on the configuration. Through the results presented here and the on-going effort of the Fix CIP collaboration, software should aim to converge upon consistent stereochemistry naming. An Open CIP software tool could provide “blessed” stereochemistry configuration names and provide a standard algorithm implementation for other vendors to integrate or adapt. Comparing Cahn-Ingold-Prelog Rule Implementations Rule 1 a. Higher atomic number precedes lower b. An atom node duplicated closer to the root ranks higher than one duplicated further Rule 2 Higher atomic mass number precedes lower Rule 3 Z precedes E and this precedes nonstereogenic (nst) double bonds Rule 4 a. Chiral stereogenic units precede pseudoasymmetric stereogenic units and these precede nonstereogenic units (R = S > r = s > nst) b. When two ligands have different descriptor pairs, the one with the first chosen like descriptor pairs has priority over the one with a corresponding unlike descriptor pairs c. r precedes s Rule 5 An atom or group with descriptor R has priority over its enantiomorph S Stereochemistry in Databases chebi_154 chembl_23 pubchem pubchem_substance eMolecules170601 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 % of Dataset Dataset Count 0 1 2 3 4 5 6 7 8 9 eMolecules (June 2017) PubChem Substance PubChem Compound (Aug 2017) ChEMBL 23 ChEBI 154 14 million records 234 million records 93 million records 1.7 million records 95 thousand records chebi_154 chembl_23 pubchem pubchem_substance eMolecules170601 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 % of Dataset Dataset Count 0 1 2 3 4 5 6 7 8 9 Number of Stereogenic Units + chebi_154 chembl_23 pubchem pubchem_substance eMolecules170601 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 % of Dataset Dataset Count 0 1 2 3 4 5 6 7 8 9 The number of defined stereogenic units per molecule varies between databases. The application of Rule 1a to the digraph for 2-butanol ranks the out edges connected to the root as giving the label S (4 > 2 > 5 are anticlockwise looking towards 6). ChEBI ChEMBL eMolecules PubChem Compound1 PubChem Substance Rule 1a 281K 99.6% 1.8M 98.6% 2.4M 97.0% 53.5M 100.0% 93.1M 98.7% Rule 1b 4 1 164 255 Rule 2 14 3,565 6,789 Rule 3 29 3 441 36 45 Rule 4a 122 126 273 4 12,770 Rule 4b 563 0.2% 4,037 0.2% 3,188 0.1% 125K 0.1% Rule 4c 19 558 Rule 5 285 0.1% 23.4K 1.2% 69K 2.8% 15 1.1M 1.2% Total 282K 1.9M 2.4M 53.5M 94.3M The majority of stereogenic units are constitutionally asymmetric and can be ranked using Rule 1a. However, in some datasets the number of stereogenic units requiring Rule 4b and 5 can be significant. I II III IV V VI VII VIII IX X XIa XIb XII XIII Centres 2.0 R R R R R R R R R r R R r R JMol 14.20.3 R R R R R R R R R r R R r R ACD/ChemSketch 14.05beta R R R R R R R R R r R R r R Balloon 1.6.5beta R R R R R R R R R r R R r R KnowItAll ChemWindow 2018 R R R R R R R R R r R R r R5 ChemDraw 16.0 R R R R S R R R R r R R r R BIOVIA Draw 2017 R R R - R R R R R -1 R R -1 R MarvinSketch 17.17 R - - - S R - R - r R R r - Indigo 1.3.0Beta.r16 -2 R - - R - R R R r S R - - RDKit 2017.03.03 S R S R S R R S R R R R - - DataWarrior 4.6.0 R R R - S R R S R R R3 R - - CACTVS (NCI Resolver Aug 17) R R S - S4 R R S R R S R - - OPSIN 2.3.1 R R R R R - - - - - S R - - LexiChem (OEChem) 20170613 R R - - R - - - - - S R - - ChemDoodle 7.0.2 R R - - S - - s - r S R - - CDK 2.0 - R R5 - S - - - - - S R - - JUMBO 6 R - S - - - - - - - S S - - Constitutional (Rule 1a, 1b, 2) Geometrical + Topographical (Rule 3,4a,4b,4c,5) Special (Mancude, Aux Descriptors) 1. Pseudoasymmetric r/s labels not displayed but must be calculated due to answers given for IX and XIII 2. Runtime error occurs 3. Impossible to test as different Kekulé forms are normalised 4. R in CACTVS since Feb 2015, NCI resolver is old version 5. Other descriptor is assigned differently A set of fourteen structures was collected to identify differences between software implementations. The structures were selected to cover all the sequence rules and their applications to special cases. Eight sequence rules (in essence) Fix CIP Collaboration Since submitting this work for presentation the developers: Centres, JMol, ACD/ ChemSketch, and Balloon have begun a collaboration. We are in the process of submitting for publication an extended in-depth validation set and proposing sequence rule refinements and additions where they are required. 1As part of the PubChem Compound’s processing, non-constitutional stereochemistry is removed: for example the nine stereoisomers of inositols are all represented by CID 892. Atoms connected by double and triple bonds as well as ring closures result in duplicated nodes in the digraph. In the structure below atoms 5 and 6 appear twice and atom 1 (the root) appears three times. Due to this duplication, complex ring systems can generate exponentially large digraphs that are not computationally tractable. Further complexity in digraphs is caused by the use of fractional atomic numbers in mancude ring-systems and assignment of auxiliary descriptors for applying Rules 3-5. H OH H H H H H H H H H 1 7 6 5 (1) (1) 65234 O O 3 4 2 1 6 5 7 7 O H H H H H H H H H 321 5 4 6 1 2 3 5 6 4 H

×