Daylight and Discovery How do I impress the boss when I get back? 11/18/2018

What is Discovery? A constant fight against the hedgehogs!! 11/18/2018

What have I learned this week? Above all you have learned new languages that allow you to communicate chemical concepts to, and between, machines. These languages also allow you to communicate these concepts via machines to your colleagues. You have also learned about other descriptions of a molecular structure, such as fingerprints. 11/18/2018

Language recap SMILES SMARTS SMIRKS (FINGERPRINTS) 11/18/2018

SMILES SMILES contains the same information as might be found in an extended connection table. The primary reason SMILES is more useful than a connection table is that it is a linguistic construct, rather than a computer data structure. SMILES is a true language, albeit with a simple vocabulary (atom and bond symbols) and only a few grammar rules. SMILES can be canonicalised. I.e. there is a unique, universal “name” for a structure SMILES representations of structure can in turn be used as “words” in the vocabulary of other languages designed for storage and retrieval of chemical information .E.g HTML, XML or query languages such as SQL. 11/18/2018

SMILES syntax [atom]bond[atom] etc atom : ‘[‘ <mass> symbol <chiral> <hcount> <sign<charge>> <‘:’class> ‘]’ ; bond : <empty> | ’-’ | ‘=‘ | ‘#’ | ‘:’ | ‘.’ Common elements, in the organic subset B,C,N,O,P,S,F,Cl,Br,I, in their lowest common valence state(s), can be written without brackets. If bonds are omitted, they default to single or aromatic, as appropriate, for juxtaposed atoms. 11/18/2018

Example SMILES 11/18/2018

SMARTS In the SMILES language, there are two fundamental types of symbols: atoms and bonds. Using these SMILES symbols, one can specify a molecule's graph (its "nodes" and "edges") and assign "labels" to the components of the graph (that is, say what type of atom each node represents, and what type of bond each edge represents). The same is true in SMARTS: One uses atomic and bond symbols to specify a graph. However, in SMARTS the labels for the graph's nodes and edges (its "atoms" and "bonds") are extended to include "logical operators" and special atomic and bond symbols; these allow SMARTS atoms and bonds to be more general. For example, the SMARTS atomic symbol [C,N] is an atom that can be aliphatic C or aliphatic N; the SMARTS bond symbol "~" (tilde) matches any bond 11/18/2018

Example SMARTS 11/18/2018

Useful SMARTS Heavy atom [!$([#6,#7,#8,#9,#15,#16,#17,#35,#53])] Rotatable bonds [!$(*#*)&!D1]-&!@[!$(*#*)&!D1] Secondary amides [N&H1&D2]-&!@[#6&X3] H-donors [!#6;!H0] H-acceptors [$([!#6;+0]);!$([F,Cl,Br,I]);!$([o,s,nX3]);!$([Nv5,Pv5,Sv4,Sv6])] Isolating carbons [#6;!$(C(F)(F)F);!$(c(:[!c]):[!c]);!$([#6]=,#[!#6]);!$([#6;!+0])] Stereo atoms [$([X4&!v6&!v5;H0,H1]),$([SX3]([#6])([#6])~O)] Stereo bonds [CX3;!H2]=[CX3;!H2] Stereo allenes [CX3;H0]=C=[CX3;H0,H1] 11/18/2018

Rotatable bonds [!$(*#*)&!D1]-&!@[!$(*#*)&!D1] An atom which is NOT triply bonded to another atom AND NOT 1-connected ( I.e. Not terminal ) Bonded by A single bond AND NOT a ring bond to the same type of atom 11/18/2018

Chemical Information Concepts in Discovery Matching Total Partial Similarity Qualitative Quantitative Both matching and similarity are opinions as they depend on descriptors. 11/18/2018

Filtering Quite often you may wish to eliminate compounds which are inappropriate for some activity or test. E.g. Delete any molecule from a list which contains a “heavy metal” i.e. a non-common element > $CONTRIB/smarts_filter -v \ ‘[!$([#6,#7,#8,#9,#15,#16,#17,#35,#53])]’ 11/18/2018

Counting things Count matches to patterns defined in SMARTS Molecular formula H-donors H-acceptors Rotatable bonds Chiral centres Rings Fragments 11/18/2018

Example Molecular formula C13H22N4O3S H-donors 2 H-acceptors 6 Rotatable bonds 8 Chiral centres 1 Rings 1 Fragments 6 11/18/2018

Estimating Measured Properties Any property which is an additive constitutive property of a molecule can be calculated by counting the matches of the constituent patterns lookup the weight for the pattern summing the products of the count and individual pattern weights. apply any correction factors 11/18/2018

Examples of properties to calculate Molecular Weight logP Parachor Molar Volume Molar Refractivity ………. 11/18/2018

Molecular weight: a simple example Molecular formula (count(atom(i))*atomic_weight(atom(i))) Accuracy depends on accuracy of atomic weights ( IUPAC) C13H22N4O3S 314.45 (average molecular weight ) 314.141235 ( accurate mass of commonest isotope) 11/18/2018

CLOGP: A more complicated example Algorithmic definition of fragment Pattern = NOT an isolating carbon Match the pattern to find all the fragments Look up the fragment value(s) ( if it exists ) using the unique string(s) from the match. Accumulate the values for fragments and non-fragments (isolating carbons). Correct for proximity 11/18/2018

CLOGP example 2 * Cl +1.880 guanidyl –1.930 2 * C +0.390 6 * c +0.780 7 * H +1.589 Proximity –0.984 Total +1.727 11/18/2018

Estimating values for concepts Flexibility Ratio of number of rotatable bonds to total number of bonds Rigidity Molecular similarity between original molecule and molecules formed by breaking all rotatable bonds Difficulty of synthesis Ratio of number of potential chiral centres weighted for rings to total number of heavy atoms in a molecule 11/18/2018

Example Flexibility 0.38 Rigidity 0.3819 Difficulty of synthesis 0.05 11/18/2018

Example Flexibility 0.38(0.00) Rigidity 0.3819(1.00) Difficulty of synthesis 0.05 (0.85) Figures in parentheses for morphine 11/18/2018

Relationships between compounds Compound sets Molecular descriptors Fingerprints etc Similarity measures Tanimoto etc Clustering Jarvis-Patrick etc 11/18/2018

Relationships between compounds Mixtures Molecular descriptors Modal Fingerprints etc Similarity measures Tanimoto etc Prototypes Family Resemblance 11/18/2018

Relationships between compounds Reactions Molecular descriptors Fingerprints Rôles Schemes/pathways Similarity and clustering 11/18/2018

Examples Creating a spreadsheet of properties. Non-standard fingerprinting and similarity. 11/18/2018

Don’t let the hedgehogs take over….. 11/18/2018

Don’t let the hedgehogs take over….. 11/18/2018