Talk at SMASH 2011

Automatic Generation ofNegative Control Structures for Automated Structure Verification Systems Gonzalo Hernández SMASH 2011 Chamonix,France

Outline Goal Similarity Calculation Overview NMR Specific Fingerprint Development Method Validation Applications Database Searching Automated Structure Verification (ASV)

Goal• To develop a method that given a target chemical structure would rank other proposed structures based on the expected similarity of their NMR data, without an a priori knowledge of that data. Increased Similarity

How to Achieve Our Goal• Calculate a molecular similarity coefficient predictive of NMR data similarity.• Develop an NMR-specific molecular fingerprint

Molecular Similarity vs. NMR Data SimilarityMolecular Fingerprints• A molecular fingerprint is a collection of descriptors that is used to characterize a molecule. For example, the number and type of functional groups, molecular formula, etc.• Different metrics can be calculated between fingerprints to find their similarity or dissimilarity.• Most common fingerprints are: Public MDL keys, fcp4, fragment-based, etc. F F S O S O H3C OH F O O Cl CH3 Cl CH3 FNMR Data Similarity• Which two molecules are structurally most similar?• Which molecules would present the most similar NMR data?• How to answer the previous question without knowing the actual NMR data.

NMR-Specific Molecular Similarity CoefficientSimilarity based on Chemical Environments Around Carbon Atoms• Define the most common chemical environments up to three shells emanating from a carbon atom• Assemble them as bits of a fingerprint• Count how many times each fingerprint bit (environment) is present in each molecule• Calculate similarity between two molecules as the Euclidean distance between two fingerprints [CH1]([CH3])(OC)[CH1](C)CSMARTSSmiles ARbitrary Target Specification (SMARTS) is alanguage for specifying substructural patterns in Omolecules.[#6] any Carbon atom NH[CH3] Methyl group[n;!H0] pyrrole-type Nitrogen[#7,#8;!H0] hydrogen bond donor [cH1]([cH0](C)c)[cH1]c

Fingerprint Development1. Generate all combinations of SMARTS code strings Bi ( bj ( Rk ) )l Where: Bi = { [CH3], [CH2], [CH1], [cH1] } bj = { -, =, #, : } Rk = { C, N, O, S, F, Cl, Br, I, c, n, o, s } l = i – j + 1, l > 02. Extract all chemical environments up to three shells from large compound database – Database contained about 4.6 million compounds, extracted from PubChem, for a total of 82 million chemical environments

Method Validation Test set of 100 commercial compounds Calculate pairwise Molecular Similarity between all pairs (4950 pairs total) Predict 1H, 13C, and construct 1H-13C HSQC data Calculate Spectral Similarity (1D and 2D binning) Compare Molecular Similarity vs Spectral Similarity for all pairs

Molecular Similarity vs. Spectral Similarity  Similarity measured as distance. Smaller numbers mean greater similarity  Molecular fingerprint contains 28,833 chemical environments (bits)  Spectral Similarity calculated used 2D binning and euclidean distance metric

1H-1D NMR Data • Predicted similarity was calculated using a 1H specific fingerprint containing 100,000 unique three-shell chemical environments (bits) • Actual similarity was calculated as a 1D binning of the predicted 1H-1D spectra • In both cases the metric used was Euclidean distance between fingerprint bits

13C-1D NMR Data • Predicted similarity was calculated using a 13C specific fingerprint containing 200,000 bits • Actual similarity was calculated as a 1D binning of the predicted 13C-1D spectra • In both cases the metric used was Euclidean distance between fingerprint bits

1H-13C HSQC 2D NMR Data • Predicted similarity was calculated using a H-C correlation specific fingerprint containing 50,000 bits • Actual similarity was calculated as a 1D binning of the predicted 13C-1D spectra • In both cases the metric used was Euclidean distance between fingerprint bits

Test Set (Database Search) (MW <= 250 Da, 1 CH3, 3 CH2, 1 CH, 4 Ar) 0 0 0 Pairwise similarity O OH 20 O O H N 20 Br NH2 20 a b c d e f g h i j N 40 H 40 40 10 O f g h i j N 60 60 60 6 f1 (ppm) f1 (ppm) f1 (ppm) 80 80 80 8 5 a 100 120 b 100 120 c 100 120 4 140 140 140 3 6 160 160 160 2 Molecule B10 8 6 4 2 0 10 8 6 4 2 0 10 8 6 4 2 0 f2 (ppm) f2 (ppm) f2 (ppm) 0 0 0 1 a b c d e 20 20 20 4 0 HN 40 N 40 O H N 40 H H O N 60 60 N O 60 H f1 (ppm) 2 f1 (ppm) f1 (ppm) 80 80 80 d 100 120 e 100 120 f 100 120 140 140 0 140 0 2 4 6 8 10 160 160 16010 8 6 4 2 0 10 8 6 4 2 0 10 8 6 4 2 0 Molecule A f2 (ppm) f2 (ppm) f2 (ppm) 0 0 0 0 O O 20 20 20 20 N O 40 40 40 O 40 N O 60 60 60 O 60 H N NH2 N f1 (ppm) f1 (ppm) f1 (ppm) f1 (ppm) 80 H 80 80 80 OH g 100 120 h 100 120 i 100 120 j 100 120 140 140 140 140 160 160 160 16010 8 6 4 2 0 10 8 6 4 2 0 10 8 6 4 2 0 10 8 6 4 2 0 f2 (ppm) f2 (ppm) f2 (ppm) f2 (ppm)

Automated Structure VerificationAre Chemical Structure and NMR data consistent with eachother?  Procedure:  Predict NMR data from proposed structure  Compare to experimental data (1H, 1H-13C HSQC)  Calculate matching score  Not seeking full structure elucidation or accurate assignmentsWhy doing this?  Best way to deal with large number of simple compounds (i.e. libraries, reagents, etc.)  Leave interesting problems for manual analysis

ASV of Negative Control Structures 1.00 0.90 PC-1 0.80 0.70 PC-2 PC-3 Test Set 10 Positive Control StructuresASV Score 0.60  0.50  5 Negative Control structures generated 0.40 0.30 automatically 0.20  ASV run on all 6 structures against experimental 0.10 NMR data (1H-1D and HSQC) 1 0.00 0.00 5.00 10.00 15.00 20.00 25.00 Molecular Similarity 1.00 1.00 1.00 0.90 0.90 PC-7 0.90 PC-9 PC-4 PC-10 0.80 PC-5 0.80 PC-8 0.80 PC-6 0.70 0.70 0.70 ASV Score ASV ScoreASV Score 0.60 0.60 0.60 0.50 0.50 0.50 0.40 0.40 0.40 0.30 0.30 0.30 0.20 0.20 0.20 0.10 0.10 0.10 0.00 0.00 0.00 2.00 6.00 10.00 14.00 18.00 0.00 5.00 10.00 15.00 20.00 25.00 0.00 5.00 10.00 15.00 20.00 0.00 4.00 8.00 12.00 16.00 20.00 Molecular Similarity Molecular Similarity Molecular Similarity 1 ASV was run by Phil Keyes at Lexicon Pharmaceuticals using ACDLabs ASV system

Negative Controls for PC1 1.00 0.90 PC-1 0.80 PC-2 0.70 PC-3 ASV Score 0.60 0.50 0.40 0.30 0.20 0.10 0.00 0.00 5.00 10.00 15.00 20.00 25.00 Molecular Similarity

Negative Controls for PC5 1.00 0.90 PC-4 0.80 PC-5 PC-6 0.70 ASV Score 0.60 0.50 0.40 0.30 0.20 0.10 0.00Positive Control 0.00 5.00 10.00 15.00 20.00 25.00 Molecular Similarity

ASV is a Binary Classifier• The yellow band is a myth• A Binary Classifier is a system that selects between two options• Binary classifier is a well understood, well developed area of statistical analysis with many metrics at our disposal• Used in many fields including, decision making, machine learning, signal detection theory• Set your strategy (false positive/negative tolerant) and live with it

Summary Developed a molecular similarity method predictive of NMR data similarity for 1H-1D, 13C-1D and 1H-13C HSQC data Similarity calculation can be used for other purposes like CASE studies if linked to a structure generator The confidence level of an autoverification can be calculated by challenging the system with negative control structures of known similarity to the proposed structure

AcknowledgmentsLexicon Pharmaceuticals Modgraph Giovanni Cianchetta Jeff Seymour Phil Keyes FundingMestreLab Carlos Cobas Chen Peng Open Source ComunityACDLabs Ryan Sasaki Sergey Golotvin OpenBabel

Talk at SMASH 2011

by Gonzalo Hernandez

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