Outline. Setting the scene. Retrosynthesis tool: ICSYNTH. Forward reaction prediction tool: ICFRP. Conclusions. o CASD and InfoChem o New motivations

Transcription

1 1 / 27 Cmputer-aided synthesis design (CASD) and frward reactin predictin tls fr bth idea generatin in new synthesis rute planning and fr de nv mlecule design V. Eigner-Pitt, F. Huerta*, M. Hutchings, H. Saller, P. Lew InfChem GmbH, Landsberger Strasse 408, Munich, 81241, Germany *Chemntia AB, Södertällje , Sweden InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

2 2 / 27 utline utline Setting the scene CASD and InfChem ew mtivatins Retrsynthesis tl: ICSYTH Wrkflw verview Examples Twistane xaspirketne Frward reactin predictin tl: ICFRP Wrkflw verview Applicatin fields Interfaces and examples Cnclusins InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

3 3 / 27 utline utline Setting the scene CASD and InfChem ew mtivatins Retrsynthesis tl: ICSYTH Wrkflw verview Examples Twistane xaspirketne Frward reactin predictin tl: ICFRP Wrkflw verview Applicatin fields Interfaces and examples Cnclusins InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

4 4 / 27 Setting the scene CASD and InfChem ver Time Cperatin with AstraZeneca Prcess Develpment Launch f Synthesis Tree Search (CDRM) Develpment f ICMAP and CLASSIFY InfChem acquires rights fr the SPRESI data Cmprehensive synthesis planning using multiple reactin search algrithms Valentina Eigner-Pitt 1, Jsef Eiblmaier 1, Hans Kraut 1, Heinz Saller 1, Peter Lew 1, and Guenter Grethe 2 Rll-ut fr 50 scientists at AZ Defined as business critical in prcess develpment department king-fr-winter-weirdness-3.html Intrducing Rute Designer v1.0 A Peter Jhnsn 1, Zslt Zslds 2,Anik Simn 2, Darryl Reid 2, James Law 2, Yang Liu 2, Sing Yng Khew 2, and Hward Y. And 3 InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

5 5 / 27 Setting the scene ew Mtivatins Algrithms / sftware Atm-atm-mapping Reactin centre i/d Reactin classificatin Fast search engine Extensive reactin databases e.g. SPRESI (InfChem): 4 M reactins Cmputer hardware Pwerful Inexpensive etwrked Secure InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

6 6 / 27 utline utline Setting the scene CASD and InfChem ew mtivatins Retrsynthesis tl: ICSYTH Wrkflw verview Examples Twistane xaspirketne Frward reactin predictin tl: ICFRP Wrkflw verview Applicatin fields Interfaces and examples Cnclusins InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

7 / 27 ICSYTH: Cncept ICSYTH: Wrkflw verview 1. Pre-prcessing R1 11 R2 12 Template (2 levels): 4 Remve bnd 1-3 Transfrm: Make new Remve single bnd between bnd atms between 3 and 6. atms 3 and 5 Remve bnd 1-2 Decrease bnd rder f duble bnd 2=4 by 1. Make new single bnd between atms 3 and 4 Make new single bnd between atms 2 and 6. Add grup t atm 3: -H Autmatic transfrm extractin (ICMAP/CLASSIFY) Transfrm library 2. Synthesis Planning Target mlecule Lkup stred examples Reactin database e. g. SPRESI prprietary databases cmmercial databases Reactin 1: Precursr(s) 1 Transfrm x Transfrm x Reactin 2: Reactin n: Precursr(s) 2... Precursr(s) n Transfrm y Transfrm n Target mlecule Transfrm y Transfrm n InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

8 8 / 27 ICSYTH: Examples Examples Publicatin in rganic Prcess Research and Develpment: Rute Design in the 21 st Century: The ICSYTH Sftware Tl as an Idea Generatr fr Synthesis Predictin 2) 2) Bøgevig, Federsel, Huerta, Hutchings, Kraut, Langer, L w, ppawsky, Rein, and Saller Chemical Develpment, AstraZeneca R&D, Macclesfield, SK10 2A Cheshire, U.K., Chemntia AB, S derta lje, Sweden, InfChem GmbH, D Mu nchen, Germany Twistane Since 50 years an interesting prblem in synthesis Synthesis teaching tpic in many rganic chemistry curses Rutinely used during develpment t really interesting frm the prcess develpment pint f vue xaspirketne Prblem fr AZ Scale-Up Lab in Södertälje Late intermediate t a series f ptential Alzheimer s treatements Medicinal Chemistry synthesis path nt suitable fr scale-up InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

9 9 / 27 ICSYTH: Examples Example: Twistane InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

10 10 / 27 ICSYTH: Examples Example: Twistane 3 f the first 5 suggestins in step 1 crrespnd t key intermediates in published synthesis reassuring fr new users gratifying fr sftware develpment (in terms f e.g. algrithm and ranking capabilities)...but largely irrelevent frm the idea generatin pint f view ew transannular C-C bnd frmatin acrss decalin precursrs invlved in:...mst f the new suggested rutes...and in the shrtest ne reprted in literature t surprising because already histrically identified as mst strategic bnd Cnsideratins in precursr ranking within ICSYTH Applicatin f cmplexity measure t identify which bnd(s) lead t the greatest mlecular simplificatin in the retr directin (bnd-breaking), cupled with reactins resulting in multiple bnd frmatin Mst favrable f 4 pssible C-C breakages in twistane case results in decalin skeletn precursr Less attractive bnd-making cmbinatin are mre cmplex and lead t mre cmplex synthesis InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

11 11 / 27 ICSYTH: Examples Example: xaspirketne Med Chem rute nt suitable fr scale-up: Yields nt reprducible and < 10% Sme reagents nt ptimal (TMSC, LiHMDS) Tedius chrmatgraphic separatin frm mixture Additinal task aspect: Crrect stereismer generatin, critical fr bilgical activity f final cmpund At least easy islatin methd f desired ismer Discnnectin f bnds a, b, c and d studied: a and b discnnectins appealing at first sight...but use f nn-desired reagents invlved ICSYTH uncnventinal suggestin: n intuitive discnnectin f c in last step InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

12 12 / 27 ICSYTH: Examples Example: xaspirketne InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

13 13 / 27 ICSYTH: Examples Example: xaspirketne Initial cnventinal retrsynthetic analysis culd nt identify the illustrated bnd c discnnectin Althugh the reprted precedent culd nt be used as such, a new rute culd be readily develped Cnclusin: ICSYTH used as idea generatr identifies uncnventinal and unusual transfrmatins that lead t nt expected but in this case highly relevant slutins InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

14 14 / 27 utline utline Setting the scene CASD and InfChem ew mtivatins Retrsynthesis tl: ICSYTH Wrkflw verview Examples Twistane xaspirketne Frward reactin predictin tl: ICFRP Wrkflw verview Applicatin fields Interfaces and examples Cnclusins InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

15 r 15 / 60 Frward reactin predictin tl: ICFRP Sftware Reactin Predictin Tls: ICSYTH, ICFRP Target Starting material + H Br + S Br + H Br + S Br Br + H Br + S Br + H Br + S B Br I I Br Br I + H Br + S Br + H Br + S Br I + H Br + S Br InfChem Cpyright 2015 Meeting Merck - InfChem, Darmstadt, July 22, 2015

16 / 27 ICFRP: Wrkflw verview ICFRP: Wrkflw verview 1. Pre-prcessing Template (2 levels): R1 11 R Remve bnd 1-3 Transfrm: Make new Remve single bnd between bnd atms between 3 and 6. atms 3 and 5 Remve bnd 1-2 Decrease bnd rder f duble bnd 2=4 by 1. Make new single bnd between atms 3 and 4 Make new single bnd between atms 2 and 6. Add grup t atm 3: -H Autmatic transfrm extractin (ICMAP/CLASSIFY) 2. Reactin Predictin Transfrm library Lkup stred examples Reactin database e. g. SPRESI prprietary databases cmmercial databases Starting material Prduct(s) 1 Prduct(s) 2... Prduct(s) n Knwledge-based cmpund design InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

17 17 / 27 ICFRP: Applicatin fields ICFRP Applicatin Fields Reactivity mapping verview f which psitins in the cre can be mdified, and hw Scaffld mdificatin Structural changes f the cre structure Library synthesis Brad range f pssible mdificatins (including, e.g., biissteres) f a given psitin in the mlecule Different utputs btained by tailring the query strategy parameters InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

18 18 / 27 ICFRP: Interfaces ICFRP User Interfaces Knime nde Web-applicatin Pipeline Pilt cmpnent InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

19 19 / 27 ICFRP: Interfaces and examples Example 1: Knwledge-based Drug Design Prf f cncept n knwn mlecule: Diazepam 80 new suggested mlecules (with related synthesis reactins) Query cre structure Reaxys substructure search 2564 knwn related cmpunds (with assciated physicchemical prperties) InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

20 20 / 27 ICFRP: Interfaces and examples Example 1: Knwledge-based Drug Design Fingerprints calculated Identical cmpunds filtered ff (Tanimt = 1) 13 suggested prducts with a Tanimt Physicchemical prperties calculated and cmpared with reprted nes ew suggested mlecules shw similar prperties t the knwn nes InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

21 21 / 27 ICFRP: Interfaces and examples Example 2: Knwledge-based Drug Design Prf f cncept inspired by de nv design using reactin vectrs Example frm J. Chem. Inf. Mdel., Vl. 49,. 5, 2009, Penicillin G InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

22 22 / 27 ICFRP: Interfaces and examples Example 2: Knwledge-based Drug Design ICFRP with medium precisin ICFRP with high precisin InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

23 23 / 27 ICFRP: Interfaces and examples Example 3: Multistep Synthesis Starting frm a Building Blck InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

24 24 / 27 utline utline Setting the scene CASD and InfChem ew mtivatins Retrsynthesis tl: ICSYTH Wrkflw verview Examples Twistane xaspirketne Frward reactin predictin tl: ICFRP Wrkflw verview Applicatin fields Interfaces and examples Cnclusins InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

25 25 / 27 Cnclusins Cnclusins ICSYTH is used as idea generatr fr retrsynthetic analysis helps identifying synthesis rutes that g beynd knwn chemist-derived suggestins It is a unique predictive tl fr rute design in Chemical Develpment at AstraZeneca Unwanted/chemically incrrect suggestins generate fastidius nise Imprvements under develpment: Stere-chemistry handling Better chemical selectivity and reactin cnflict predictins ew algrithm t enable starting material-based strategies Yunger ICFRP has prved its ptential in assisting research scientists in drug discvery and drug design by generating new valuable candidates in regards f: nvelty chemical diversity synthesizability InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

26 26 / 27 Cnclusins Cnclusins Retrsynthesis, synthesis planning and frward reactin predictin: When will cmputers meet the needs f the synthetic chemist? InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015

27 27 / 27 Cnclusins Acknwledgements H. Saller, M. Hutchings (ICSYTH) AZ Prcess Develpment Team F. Huerta (ICFRP) The InfChem Team 4.bp.blgspt.cm/.../s1600/thank-yu.jpg InfChem GmbH: inf@infchem.de InfChem Cpyright 2015 ACS Fall atinal Meeting, Bstn, August 17, 2015