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Matched-Pairs Closing the Circle

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Talk given 2016-03 | CUP XVI | Santa Fe, NM
https://www.eyesopen.com/events/2016/03/cup-16
matched-pairs and internal H-bonds

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Matched-Pairs Closing the Circle

  1. 1. Matched Pairs - Closing the Circle
  2. 2. Secondment to work with Andrew Grant, Alderley Park (2002-2003) Shared office with Pete Kenny – talked a lot ….about a method to bring the most interesEng pairs of molecules to the top those for which the smallest structural change give rise to the biggest change in, say, affinity. For any [matched]-pair of molecules i and j: My Matched-Pair Journey where ΔAij is the ra,o of the affini,es, Sij is the similarity of the two molecules From manual to automaEzed Medicinal Chemistry Cheminforma5cs (OEChem)
  3. 3. Cheminforma5cs – Tools AstraZeneca has a long history of developing various Breaking-Bonds/R-group tools, in parEcular matched-molecular pair tools: WizePairZ – to exploit MMPs with unspecified cores in Medicinal Chemistry Periscope – to encode and search Markush structures in chemical patents FOG analysis – key compound predicEon in patents using frequency of R-groups Scaffold Hopping – a tool for scaffold hopping by fragment replacement in 3D SAR spoZer – web-based tool to find “interesEng” pairs of molecules Avesome – to exploit MMPs with specified cores in Medicinal Chemistry Matsy – using Matched Molecular Series as a tool to opEmize biological acEvity … + 10
  4. 4. Cheminforma5cs – Impact Used in prospecEve designs, facilitaEng development of candidate drugs Johansson, A. et al “Discovery of …AZD1979…” J.Med.Chem ASAP, 2016 I did that pic! Fame and glory J Several independent publicaEons, and JMedChem twiZer background Boström, J. et al “Oxadiazoles in Medicinal Chemistry” J.Med.Chem 2012, 55, 1817-1830 Binding Affinity: 80 nM Log D: 3 HLM Clint: 20 µl/min/mg Binding Affinity: 40 nM Log D: 2 HLM CLint: 10 µl/min/mg 1,3,4-oxadiazolshowed beZer properEes than 1,2,4-oxadiazoles in terms of lipophilicityes, solubility, HLM Clint and hERG O O N N R1R2 O N N O R1R2
  5. 5. Social behaviors Drug design not always that raEonal: para-subsEtuEon, amide-bond/Suzuki couplings, … Boström & Brown ”Stuck in a rut with old chemistry”, Drug Discovery Today, 2016, Guest Editorial, ASAP Brown & Boström ”Analysis of Past and Present SyntheEc Methodologies on Medicinal Chemistry: Where Have All the New ReacEons Gone?” J.Med.Chem, 2016, ASAP Brown & Boström ”Understanding Our Love Affair with p-Chlorophenyl: Present Day ImplicaEons from Historical Biases of Reagent SelecEon” J.Med.Chem, 2015, 58, 2390. Russell Crowe as John Nash in “A BeauEful Mind” can see paZerns where there are no paZerns. By applying hypothesis- based approaches – conducEng experiments with testable predicEons, knowledge can supersede storytelling
  6. 6. Matched Pairs – Closing The Circle What’s the deal with medicinal chemists, internal H-bonds and ring-closing? Seinfeld drug designers like rings Behaviors – para-subsEtuEon, amide-bond/Suzuki couplings, and… Boström & Brown ”Stuck in a rut with old chemistry”, Drug Discovery Today, 2016, Guest Editorial, ASAP Brown & Boström ”Analysis of Past and Present SyntheEc Methodologies on Medicinal Chemistry: Where Have All the New ReacEons Gone?” J.Med.Chem, 2016, ASAP Brown & Boström ”Understanding Our Love Affair with p-Chlorophenyl: Present Day ImplicaEons from Historical Biases of Reagent SelecEon” J.Med.Chem, 2015, 58, 2390.
  7. 7. Rings Present in Drug Databases 1.3% 98.7% ChEMBL 0.9% 99.1% AstraZeneca any ring-size and type (aliphaEc/aromaEc), ring-processing using the OEChem funcEon OEFindRingAtomsAndBonds to determine which atoms and bonds are members of one or more rings (and which are acyclic) Taylor, et al ”Rings in Drugs” J. Med. Chem., 2014, 57, 5845 (frameworks, frequencies) 4.8% 95.2% Known Drugs* Compounds without Ring(s) Compounds with Ring(s) Most compounds include one or more rings – drug designers like rings
  8. 8. First Hypothesis “whenever a drug designer sees an internal hydrogen he want to ring-close it” See this Make that survey a bunch of drug designers!
  9. 9. Thoughts About Ring-Closures Survey submiZed to Medicinal Chemists at three AstraZeneca sites: in Mölndal, Cambridge, and Boston
  10. 10. Survey Says – 80 % “yes” (N=41) 9 32 0 None said “no”! “if a drug designer see an internal hydrogen they want to close it” TRUE N=41 Richard Dawson
  11. 11. “The main reason for ring-closing is to gain potency” reduce entropic cost of binding by freezing the bioacEve conformaEon results in a more potent compound? See this Make that Second Hypothesis survey a bunch of drug designers…again!
  12. 12. Thoughts About Potency… Survey submiZed to Medicinal Chemists at three AstraZeneca sites: in Mölndal, Cambridge, and Boston …and what happens with lipophilicity? (lipophilicity is a cardinal property in drug discovery – it can affect many other properEes relevant in lead opEmizaEon)
  13. 13. Survey Says (Part 1) Around half (53%) say “same”, very few (8%) answer “no “, and a third (38%) answers “yes “ “same potency” got most votes me wrong“In general do you think ring-closed compounds are more potent?
  14. 14. “Closing the ring reduces entropic penalty upon binding which is why dG becomes more favorable compared to open-ring.” “You have to be lucky if the ring-closed compound is more potent. But if it is that is great.” “I think these are a case-by-case basis and no generaliza,on can be made. I think they are definitely worth making to explore. Some,mes it works some,mes it doesn't.” “Only when the right/ac?ve conforma?on is locked by the ring closure a more potent compound is seen.” “It could be more potent – experiment is king!” Survey Comments – Potency
  15. 15. Around half (57%) say “yes”, very few (10%) answer “no “, and a third (32%) answers “same“ people say “yes” lipophilicity increases Survey Says (Part 2) “In general do you think ring-closed compounds are more lipophilic?
  16. 16. “Same lipophilicity since the H-bond in the open molecule only bonds internally giving the overall H-bond capacity to be roughly the same.” “In terms of intramolecular HB they are masked and can not be counted as normal. So no major change in lipophilicity.” “It depends doesn't it?” Survey Comments – Lipophilicity
  17. 17. “it may result in a scaffold which will have a different posi,on with regard to future IP filings” “Selec,vity may differ a lot since the internal H-bonded compound may bind another target in an open non-H-bonded conforma,on.” “[yes I’d ring-close] as well as I'd like to do the opposite” Other [Important] Comments There are other aspects (IP, Selec5vity, SAR, …)
  18. 18. Ring-Closing an Autonomic Response? – is it generally effecEve or ineffecEve?
  19. 19. Big-data mining approach using Matched-Molecular Pair technology (Python/OEChem) …and potency (ChEMBL) data …and lipophilicity (IBIS) data …some other parameters
  20. 20. •  “Molecules that differ only by a small structural change” (remainder of the molecule is exactly the same). For example •  Osen easier to predict differences in a value of a property than predicEng the value itself (one reason is cancellaEon of errors). •  The observaEon of an effect across several chemical series increases our confidence that the effect is real -> general “rules of thumbs” -> future design •  Large amounts of data across are available either publicly (e.g. ChEMBL) or internally within pharmaceuEcal companies. •  Data greedy – one limitaEon is that it can only make predicEons about structural features that have precedent in the given assay. Matched-Pairs – What is it? Prazosin Terazosin Solubility: 1.1 mg/ml Solubility: 28.1 mg/ml * Water solubility for Terazosin increases significantly when going from furan to THF. As a result, improved bioavailability (90% vs 57%) and half-life (2–3 ,mes) afford longer dura,on of ac,on, and allow once-daily administra,on. Giordanetto, Boström and Tyrchan “Follow-on drugs: how far should chemists look?” Drug Discovery Today, 2011, 16 (15-16),722-732
  21. 21. Matched-Pairs – What to expect? Two most common R groups are: hydrogen [*-H], methyl [*-C] (using “Matsy”) This matched-pair is ”random”. Potency 200k MP’s pIC50’s from >5000 assays) Cohen's d effect size: 0.03 Mean: 0.03 (pIC50’s: 5.88-5.84) magic methyl…? A parEcular matched pair transformaEon is equally likely to increase acEvity as decrease it. no effect
  22. 22. Two most common R groups are: hydrogen [*-H], methyl [*-C] Lipophilicity There’s enrichment, since we expect 6250 for each if random Cohen's d effect size: 0.24 Mean: 0.28 (logD’s: 2.25 - 1.97) Matched-Pairs – What to expect? small effect magic hydrogen!
  23. 23. Summary so far… Most compounds (>95%) include one or more rings There’s a wide interest (>80%) in designing/making “rings-closed” analogs Matched molecular pairs is a powerful method for mining data •  Especially for phys-chem properEes (logD) •  Not as successful for biological acEviEes (normal distribuEons around zero)
  24. 24. Matched Pairs – Closing The Circle cheminforma5cs using SMARTS Check distances in low- energy conforma5ons 2D 3D Methods to identify internal H-bonds ring-closure pairs (2D or 3D)
  25. 25. Workflow to Detect 2D ‘Closure-Pairs’ Record molecules that hits SMARTS, tag as “open” The number of rings counted (also used to speed up search) [O;H0:1]=,-*~*~*~[N;H,H2:1] aVeryGeneralSMARTS Cl NH R3 R1 " R2 " “open” “fragments” search if fragments match +1 contain addi,onal ring Cl NH N N N checks if patch distance of connecEon points are correct all unmatched atoms required to be in a ring* à A closed-case All “open” molecules are fragmented and connecEon points monitored, as well as the path distances between connecEon points. “close” Step 1 3 rings 4 rings N R4 *any ring allowed, but restricEons on num donors/acceptors database database Py/OEChemTk (José BaEsta and Magnus Norrby) – ComputaEonally very expensive calculaEons Step 2 Step 3
  26. 26. Workflow to Detect 3D ‘Closure-Pairs’ Take all “open”-cases [internal H-bonds] in the ring-closure pairs from 2D Expand into mulE-conformaEonal ensembles (OMEGA-Tk) Check for internal H-bond distances (<3.5Å) among low-energy conformaEons Virtually all retrieved by the 3D approach – jusEfying the 2D approach* * electrostaEc ‘collapse’ of the ligand in vacuo Boström et al “ConformaEonal energy penalEes of protein-bound ligands”, 1998, J.Comput- Aided Mol. Design 12, 383-383 The importance of using solvaEon models… electrostaEcs sEll tricky to get right.
  27. 27. Potency Database – ChEMBL v20 Addi5onal closure-pair criteria •  Closure-pairs must be tested in the same assay •  RestricEons on pairs: •  ΔH-donors ≤ 2 •  ΔH-acceptors ≤ 2 •  ΔH-acceptors and H-donors ≤ 3 •  Δformal charge == 0 DB Details… •  Only use pIC50 data for binding assays “B” •  63 940 targets •  752 228 acEviEes (could be extended with 50%; 429 347 Ki values) •  323 055 disEnct compounds •  271 440 (15 ≤ heavy atom count ≤ 40) •  83 711 with a possible internal H-bond (hits SMARTS) >60k papers: 94% from Bioorg. Med. Chem. LeI., J. Med. Chem., J. Nat. Prod., Bioorg. Med. Chem., Eur. J. Med. Chem., Med. Chem. Res.
  28. 28. pIC50 (ChEMBL) Closure-Pairs Normally distributed around zero - equally likely to gain potency as loosing potency. Δ pIC50 ”close” more potent ”open” more potent N = 2200 (850 uniq) Counts pIC50 (”open”) – pIC50 (”closed”) = 0.05 (6.33-6-28) Sama analysis on internal data more or less iden,cal – no “file-drawer” effect
  29. 29. Not all internal H-bonds are equal SMARTS defini5ons – adding context [O;H0:1]=[C]-[A,a;X4]~[A,a;X4]-[O;H:1] ACCcarbonyl_LinkerSp3_DONhydroxy_Dist5 [O;H0:1]=[C]-[A,a;X4]~[A,a;X4]-[N;H,H2:1] ACCcarbonyl_LinkerSp3_DONnitrogen_Dist5 [O;H0:1]=[C]~[A,a;X3]-[O;H:1] ACCcarbonyl_LinkerSp2_DONhydroxy_Dist4 [O;H0:1]=[C]~[A,a;X3]-[N;H,H2:1] ACCcarbonyl_LinkerSp2_DONnitrogen_Dist4 Acceptors (5): carbonyl, heterocyclic N, hydroxyl, S=O, alkoxy Donors (2): hydroxl, nitrogen Linker-type (2): sp2, sp3 (aliphaEc or aromaEc) Linker-length (3): 4, 5, 6 [O;H0:1]=[C]~[A,a;X4]-[O;H:1] ACC:carbonyl Linker: sp3 DON: hydroxy Dist4: (easy to customize) 60 SMARTS combinaEons strong poor good
  30. 30. Some types of ring-closures increases potency on average? Calculate cohen’s effect size for all SMARTS (incl pairs>20) Closure-Pairs – Potency SMARTS Mean d2 err_d d pairs ACCmetoxy_LinkerSp2_DONhydroxy_Dist4 -0.57 0.61 0.78 0.13 107 ACChydroxy_LinkerSp2_DONnitrogen_Dist4 0.36 0.37 0.61 0.11 124 ACChydroxy_LinkerSp3_DONhydroxy_Dist5 0.45 0.25 0.50 0.20 34 ACCmetoxy_LinkerSp2_DONnitrogen_Dist4 -0.23 0.25 0.50 0.15 63 ACChydroxy_LinkerSp3_DONnitrogen_Dist5 -0.32 0.23 0.48 0.11 113 ACCmetoxy_LinkerSp3_DONnitrogen_Dist5 -0.29 0.21 0.46 0.10 120 ACCcarbonyl_LinkerSp2_DONhydroxy_Dist5 0.32 0.20 0.45 0.15 55 ACCmetoxy_LinkerSp3_DONhydroxy_Dist5 0.29 0.18 0.42 0.16 47 ACChydroxy_LinkerSp3_DONhydroxy_Dist4 0.24 0.13 0.37 0.09 155 ACCcarbonyl_LinkerSp3_DONhydroxy_Dist6 0.11 0.09 0.29 0.18 35 ACCcarbonyl_LinkerSp2_DONnitrogen_Dist5 0.12 0.09 0.29 0.18 36 ACChydroxy_LinkerSp2_DONhydroxy_Dist4 -0.08 0.07 0.25 0.11 98 ACChydroxy_LinkerSp3_DONnitrogen_Dist4 -0.12 0.07 0.27 0.05 382 ACCmetoxy_LinkerSp3_DONhydroxy_Dist4 0.10 0.06 0.25 0.08 162 ACCmetoxy_LinkerSp3_DONnitrogen_Dist4 -0.08 0.05 0.23 0.05 466 Signal!? …but only 11 uniq pairs …but only 20 uniq pairs
  31. 31. There Are Many Ways to Make a Ring Internal H-bond CHEMBL1143672: Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotaEon analogues of methylphenidate. CHEMBL1203942 CHEMBL904 pIC50: 6.6 pIC50: 5.7 “The results suggest that the conforma,on of methylphenidate (MP) in which the carbonyl group of the methyl ester is H-bonded to the piperidinyl N−H may be the bioac,ve form of the molecule.” J. Med. Chem. (2007) 50:2718-2731 Displacement of [3H]nisoxeEne from norepinephrine transporter (NET) in Sprague-Dawley rat corEcal Essue at 5 uM Ring-Closed (6-ring) less potent agents [ACCcarbonyl_LinkerSp3_DONnitrogen_Dist5]
  32. 32. CHEMBL1129655: A comparaEve molecular field analysis study of N-benzylpiperidines as acetylcholinesterase inhibitors. CHEMBL333909 CHEMBL56079 pIC50: 6.1 pIC50: 7.0 “compounds have been found to inhibit the metabolic breakdown of the neurotransmijer acetylcholine (ACh) by the enzyme acetylcholinesterase (AChE) and hence alleviate memory deficits in pa,ents with Alzheimer’s Disease by poten,a,ng cholinergic transmission.” J. Med. Chem. (1996) 39:380-387 (5-ring) more potent There Are Many Ways to Make a Ring Internal H-bond Ring-Closed [ACCpyr_LinkerSp2_DONnitrogen_Dist4]
  33. 33. IdenEficaEon of a New Chemical Class of Potent Angiogenesis Inhibitors Based on ConformaEonal ConsideraEons and Database Searching CHEMBL101253 CHEMBL101683 equipotent ΔpIC50: -0.1 There Are Many Ways to Open a Ring VEGF tyrosine kinase receptors KDR and Flt-1 are targets in anEcancer “resulted in a compound with the same level of potency and selec,vity” Furet et al Bioorg.Med. Chem. LeZ. 13, (2003) 2967–2971 design [ACCcarbonyl_LinkerSp2_DONnitrogen_Dist5]
  34. 34. Closure-Pairs – logD lipophilicity (logD) increases with 0.6, on average, upon ring-closure Cohen's d effect size: 0.64 Mean: 0.6 (logD’s: 2.4 - 1.8) medium effect Calculated lipophilicity (clogP) very similar profile: 3.3 -2.4 N= 2400
  35. 35. Closure-Pairs – logD All types of ring-closures increases lipophilicity on average, some more than others SMARTS Mean Cohens d2 err_d d no pairs ACCcarbonyl_LinkerSp3_DONnitrogen_Dist4 1.20 1.49 1.22 0.38 21 ACCcarbonyl_LinkerSp3_DONnitrogen_Dist5 1.06 0.95 0.97 0.27 32 ACChydroxy_LinkerSp3_DONnitrogen_Dist5 0.78 0.91 0.95 0.13 135 ACCpyriLinkerSp3_DONnitrogen_Dist5 0.86 0.89 0.95 0.24 39 ACCpyriLinkerSp2_DONnitrogen_Dist5 0.67 0.82 0.91 0.28 27 ACCmetoxy_LinkerSp3_DONnitrogen_Dist5 0.75 0.82 0.91 0.12 152 ACCmetoxy_LinkerSp3_DONnitrogen_Dist4 0.63 0.59 0.77 0.06 567 ACChydroxy_LinkerSp3_DONnitrogen_Dist4 0.56 0.56 0.74 0.06 471 ACChydroxy_LinkerSp3_DONhydroxy_Dist4 0.47 0.49 0.70 0.12 125 ACCmetoxy_LinkerSp2_DONnitrogen_Dist5 0.39 0.47 0.69 0.26 24 ACChydroxy_LinkerSp3_DONhydroxy_Dist5 0.46 0.43 0.65 0.20 39 ACCpyriLinkerSp2_DONnitrogen_Dist4 0.37 0.40 0.63 0.13 89 ACCmetoxy_LinkerSp3_DONhydroxy_Dist4 0.44 0.40 0.63 0.08 256 ACCcarbonyl_LinkerSp3_DONhydroxy_Dist6 0.44 0.38 0.62 0.14 82 ACCmetoxy_LinkerSp3_DONhydroxy_Dist5 0.35 0.37 0.61 0.13 86 ACCcarbonyl_LinkerSp2_DONnitrogen_Dist5 0.24 0.26 0.51 0.15 64 0.60 0.64 (no pairs>20) Signal! …all uniq pairs
  36. 36. average Caco-2 (”closed”) – average Caco-2 (”open”) = -3.0 (within experimental error!) N = 60Permability SCHEMBL3813720 Caco-2 PappAB (10-6cm/s): 33.5 SCHEMBL9832404 Caco-2 PappAB (10-6cm/s): 4.0 SCHEMBL4122434 Caco-2 PappAB (10-6cm/s): 21.9 SCHEMBL4123304 Caco-2 PappAB (10-6cm/s): 1.0 GVK2154080 Caco-2 PappAB (10-6cm/s): 4.0 SCHEMBL4981036 Caco-2 PappAB (10-6cm/s): 1.1 same Two cases where ”open” form more permeable No trend observed, lipophilicity effect not reflected in permabiliEes Need more examples to draw conclusions…
  37. 37. What about Solubility? Average pSolubility (”closed”) – average pSolubility (”open”) = 0.2 N>1000 exp Aq Sol on AZ pairs ”open” more soluble”close” more soluble Solubility (Aq) decrease with 0.2, on average, upon ring-closure Δ pSolubility Counts
  38. 38. Protein-ligand complexes (X-ray) HET PDB UniProt PDB dump: 11886 ligands (all-against-all) 15 ≤ heavy atom count ≤ 40 75 pairs remove duplicates check if bind to same target (UniProt ID) present in ≤ 10 pdb’s (reagents, ATP, ADP, etc) 6 pairs (might have lost a few in translaEon)
  39. 39. Protein-ligand complexes – Example L. Zhao et al. Bioorg. Med. Chem. LeZ. 20 (2010) 7216–7221. The respecEve PDB access codes are 3PA3, 3PA4 and 3PA5 equipotent IC50 (nM) at CHK1 Design, synthesis and SAR of thienopyridines as potent CHK1 inhibitors Tanimoto Shape : 0.97 Tanimoto Shape : 0.97
  40. 40. Summary +80% of AZ drug designers want to make/design ring-closed analogs when spo…ng an internal H-bond There are many (perceived) reasons FOR and AGAINST ring-closures •  IP, potency, SAR, lipophilicity, solubility, syntheEc feasibility, permeability, curiosity,… New OEChem matched-pair code run on experimental data reveals that, •  it is on average equally likely to gain potency as loosing potency •  lipophilicity increases in general with nearly a log unit •  some paZerns give bigger effects Lots of interesEng scienEfic quesEons... •  The data-set is great source for new ideas Yes it can be an effec5ve design strategy… but consider gain vs pain

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