a systems approach to prioritizing the synthesis of new … · 2014. 12. 2. · compounds,...

Steven Muskal, Ph.D.Chief Technology OfficerSertanty, Inc.

A Systems Approach to Prioritizing the Synthesis A Systems Approach to Prioritizing the Synthesis

of New Compositions of Matterof New Compositions of Matter

Discovery results from efficient collaboration

Chemistry Biology

Informatics(modeling)

What can be made

What should be made

A systems approach requires efficient “cause-effect” feedback

That which is synthetically “feasible:”• In-house expertise• Starting material availability• Cost/time

That which is medicinally relevant, efficacious, and safe:• Potency• Selectivity• Bioavailability• Low toxicity• Cost effective

What can be made?

What should be made?

ChIP – Chemical Intelligence Platform

• Forward, prospective exploration of existing and newly coupled synthetic strategies

• “Mixing-n-matching” synthetic protocols to generate novel, synthetically accessible molecules

• Pre- and post-synthesis filtering and prioritization

• Synthesis strategies guided towards novel and medicinally relevant molecules using ePotency,eSelectivity, and eADMEtox models

“What can you make?” “What should you make?”

“What can you make?”

Working towards “what can you make?”

Step 1: Defining chemical transformations mathematically

C = T (BBA,BBB)O

R1 H

HN

R2H2N R2+

A B C

R1

Building blocks BBA, BBB , and BBD with reaction specific “introspective” filters define the scope / applicability of the transformation

E = T2(C, BBD) = T2(T1(BBA, BBB), BBD)

HN

R2

C

+O

HO R3

D

NR2

O R3

E

R1R1

Later incorporating reaction conditions (e.g. reagents, catalysts, solvents, temp., conc., time...)

4

Subset 1: Nucleophilic Aromatic Substitution Reactions

ID Depiction comments / reactants

7000 NN

N

Cl

R

R

NH

R R

N

N

N

N

R

R

R

R+

aliphatic primary or secondar amine

7001 NN

N

Cl

R

R

NH2RN

N

N

NH

R

R

R

+

aromatic primary amine

7002 NNCl R

R

R NH

R RN

NN

R

RR

R

R

+

aliphatic primary and secondary amine

7003 NNCl R

R

R NH2R N

NNH

RR

R

R

+


7004 N

N

Cl R

R

RNH

R RN

N

N

R

RR

R

R

+

2-chloropyrimidine, but not 4-chloropyrimidine aliphatic primary or secondary amine

7005 N

N

Cl R

R

R NH2R

N

N

NH

RR

R

R+

2-chloropyrimidine, but not 4-chloropyrimidine primary aromatic amine

7006 NCl

R

R R

R

NH

R RNN

R

R

R

R

R

R+

aliphatic primary or secondary amine

7007 NCl

R

R R

R

NH2R

NNH

R

R

R

R

R

+


7008 [F,Cl]

N+

OO

RR

R

R

NH

RR N

N+

OO

R

R

RR

R

R

+

aliphatic primary or secondary amine

7009 [F,Cl]

N+

OO

RR

R

R

NH2R N

H

N+

OO

RR

R

R

R

+


7010 [F,Cl]

RR

R R

NO2 NH

RRN

R

R

RR

R R

NO2+

amine aliphatic primary or secondary

7011 [F,Cl]

RR

R R

NO2 NH2R N

H

R

R

R

R R

NO2+


7012 [F,Cl]

RR

R

NO2

NO2

NH

RRN

R

R

RR

R

NO2

NO2

+

amine aliphatic primary secondary

7013 [F,Cl]

RR

R

NO2

NO2

NH2R N

H

RR

R

R

NO2

NO2

+


Subset 2: Pd-Catalyzed Aromatic Substitutions


7014 R [Br,I] NHR

R

NR

R

R+

aryl bromide / iodide; aliphatic primary or secondary amine

7015 R [Br,I] NHR

R

NR

R

R+

aryl bromide / iodide; aromatic primary or secondary amine

7018 R [Br,I] BOHOH

RR

R+

aryl bromide / iodide; aryl boronic acid

Subset 3: Functional Group Transformations


7036 R

N+

O

O

RNH2

aryl nitro

7044 NH NH

O

O R

R

N N

Cl

Cl R

R

as drawn

7045 [C,N] NHO

[C,N]R R

[C,N] N

[C,N]

Cl

RR as drawn

6

Subset 4: Amine Acylation Reactions (Amides / Carbamates)


7046 R OH

ONH

RRN

O

R

R

R+

carboxylic acids; aliphatic amines; alcohols and aromatic amines allowed, allows activated aryl halides, no alkylators

7047 R OH

ONH

RRN

O

R

R

R+

carboxylic acids; aromatic amines; not compatible with alcohols and related, no alkylators, allows activated aryl halides

7048 R Cl

ONH

RRN

O

R

R

R+

carboxylic acid chlorides, chloroformates, chloroformamidines; aliphatic amines; not compatible with alcohols or aromatic amines, no alkylayors, allows activated aryl halides

7049 R Cl

ONH

RRN

O

R

R

R+

carboxylic acid chlorides, chloroformates, chloroformamidines; aromatic amines; not compatible with alcohols and related, no alkylators, allows activated aryl halides

Subset 5: Amine Acylation Reactions (Ureas / Thioureas)


7062 N

OR N

H

RRNH

N

O

R R

R

+

aliphatic amines; aromatic amines alcohols allowed; activated aryl halides allowed; not compatible with alkylators, other nucleophiles, other acylators, acidic compounds

7063 N

OR N

H

RRNH

N

O

R R

R

+

aromatic amines; alcohols allowed; activated aryl halides allowed; not compatible with alkytators, nucleophiles, other acylators, acidic compounds

7064 N

SR NH3

NH

NH2

S

R+

ammonia precursors for thioimidazoles; aryl amines and alcohols allowed, no alkylators, other acylators, nucleophiles, acids

7065 NS

R NH2R

NH

NH

S

R R+

primary aryl amine; precursor for 2-amino-benzthioimidazole or 2-amino-benzimidazole, or related aryls; secondary aryl amines and alcohols allowed, no alkylators, other acylators, no acids, no nucleophiles

7072 N

Sfmoc NH

R

RNH

N

S

R

R

fmoc+

aryl primary or secondary amines; Precursor for thioimidazoles with FmocNCS

7073 N

Sfmoc NH

R

RNH

N

S

R

R

fmoc+

aliphatic primary or secondary amines; Precursor for thioimidazoles with FmocNCS; allows alcohols and aromatic amines

Subset 6: Formation of Diverse Heterocyclic Systems


7037 NH

O

NH2

[C,N][C,N]

[C,N][C,N]

R OH

O

R[C,N]

[C,N][C,N]

[C,N]N

O

N R

R+

any 2-amino arylamide not in a ring; any carboxylic acid; excludes acylators, alkylators, nucleophiles, other acids, activated aryl halides, aryl bromides/iodides

7038 NH

O

NH2

[C,N][C,N]

[C,N][C,N]

R Cl

O

R[C,N]

[C,N][C,N]

[C,N]N

O

N R

R+

any 2-amino arylamide not in a ring; carboxylic acid chloride, no chloroformate, carbamoyl chloride, etc.; excludes other acylators, alkylators, nucleophiles, acids, activated aryl halides, aryl bromides/iodides

7039 NH

O

NH2

[C,N][C,N]

[C,N][C,N]

R O

O

R[C,N]

[C,N][C,N]

[C,N]N

O

N R

R+

any 2-amino arylamide not in a ring; carboxylic acid methyl ester, does not allow any other ester, which is too restrictive; no differentiation between different ester reactivity; excludes acylators, alkylators, nucleophiles, acids, activated aryl halides, aryl bromides/iodides

7040 NHR

O [C,N][C,N]

[C,N]

[C,N]N

OOR

R

[C,N][C,N]

[C,N]

[C,N]

NN

O

O

R

any 2-ureido aryl methyl carboxylate not in a ring; excludes, acylators, alkylators, acids, nucleophiles, activated aryl halides, ary bromides/iodides

7041 NH

R

O [C,N][C,N]

[C,N]

[C,N]N

OOHR

R

[C,N][C,N]

[C,N]

[C,N]

NN

O

O

R

any 2-ureido aryl carboxylic acid not in a ring; excludes, acylators, alkylators, acids, nucleophiles, activated aryl halides, ary bromides/iodides

7066 [C,N]

[C,N]

[C,N][C,N]OH

NH

R

[O,S] [C,N][C,N]

[C,N][C,N]

O

NR

any 2-hydroxyaryl-(NH)-amide, thioamide, urea, thiourea, etc.; excludes, acylators, alkylators, acids, nucleophiles, activated aryl halides, ary bromides/iodides

7067 [C,N]

[C,N]

[C,N][C,N]SH

NH

R

[O,S] [C,N][C,N]

[C,N][C,N]

S

NR

any 2-mercaptoaryl-(NH)-amide, thioamide, urea, thiourea, etc.; excludes, acylators, alkylators, acids, nucleophiles, activated aryl halides, ary bromides/iodides

7068 [C,N]

[C,N]

[C,N][C,N]NH

NH

R

[O,S]

R

[C,N][C,N]

[C,N][C,N]

N

NR

R

any 2-aminoaryl-(NH)-amide, thioamide, urea, thiourea, etc.; not amido aryl amide; excludes, acylators, alkylators, acids, nucleophiles, activated aryl halides, aryl bromide/iodide

7069 [C,N]

[C,N]

[C,N][C,N]NH

NH2

R

R O

O [C,N][C,N]

[C,N][C,N]

N

NR

R

+

1,2-diamino aryl (amino-2-arylamine); carboxylic acid methyl ester, does not allow any other ester, which is too restrictive; no differentiation between different ester reactivity; exclude, nucleophiles, acids, acylators, alkylators, activated aryl halides, aryl bromide/iodide, aldehydes, other esters

7070 [C,N]

[C,N]

[C,N][C,N]NH

NH2

R

R

O [C,N][C,N]

[C,N][C,N]

N

NR

R

+

1,2-diamino aryl; aldehyde; exclude, nucleophiles, acids, acylators, alkylators, activated aryl halides, aryl bromide/iodide

8

7071 [C,N]

[C,N][C,N]

[C,N] SH

NH2R

O [C,N]

[C,N][C,N]

[C,N] S

NR+

2-mercapto arylamine; aldehyde; exclude, nucleophiles, acids, acylators, alkylators, activated aryl halides, aryl bromide/iodide, aldehydes

Subset 7: Formation of Thioimidazoles


7060 R NH2

S

R

O[Br,I]

RN

S R

R

R

+

thioamide unsubstituted; not compatible with ketones or aldehydes, alkyl bromides / iodides, sulfonyl esters, etc., acidic compounds, nucleophilic compounds

7061 NRR

NH2

S

R

O[Br,I]

R N

S R

R

N

R

R+

unsubstituted thiourea; not compatible with ketones or aldehydes, alkyl bromides / iodides, sulfonyl esters, etc., acidic compounds, nucleophilic compounds

Subset 8: Standard Deprotection Steps


7079 N

R

R

O

O

NHR

R

Fmoc deprotection, any Fmoc amine or amide aliphatic or aromatic

7080 NRR

O

O

NHR

R

any boc amine or amide aliphatic or aromatic

7081 RO

ROH

t-Bu ether, no acid or carbamate

7082 R O

O

R OH

O

t-Bu ester, not carbamate, etc, R must be carbon

7083 [O,S]

R

R

R

R [O,S]R

any trityl ether/ester, thioether/ester derivative

7084 N

R

R

R

R

R

NH

R R

any trityl amine / amide aromatic/aliphatic derivative

Filtering, filtering, filtering…

RXN Smirk with “introspective filter:”

[N;$([N;!H0](c1[#6,#7][#6,#7][#6,#7][#6,#7]c1[N;!H0;!H1])[A,a]);!$([N+]);!$(NC=,#[!#6]);!$(NC=,#[#6]);!$(N[!#6;!#1]):4]([c:11]1[c:10]([N;!H0;!H1:3]([H])[H])[a:7][a:5][a:6][a:8]1)([A,a:1])[H].[CH3]O[C;$(C(O[CH3])(=O)[A,a]);!$(C(=O)(O[CH3])[!#6]):9](=O)[A,a:2]>>[n:3]1[c:9]([n:4]([c:11]2[c:10]1[a:7][a:5][a:6][a:8]2)[A,a:1])[A,a:2]

[C,N][C,N]

[C,N][C,N]NH

NH2

R

R O

O [C,N][C,N]

[C,N][C,N]

N

NR

R

+r7069

Required: 1,2-diaminoaryl (amino-2-arylamine); carboxylic acid methylesterNot allowed: nucleophiles, acids, acylators, alkylators, activated arylhalides, aryl bromide/iodide, aldehydes, any other esters (no differentiation between reactivities of different esters)

e.g. Bulding Block Required Filters (r7069.1, r7069.2):

c(c([NH2;v3])[a])([a])[N;!H0;!$([N+]);!$(NC=,#[!#6]);!$(NC=,#[#6]);!$(N[!#6])]

[C;$(C(=O)O[CH3]);!$(C(=O)(O[CH3])[!#6])]

e.g. Bulding Block Exclude Filters (r7069.1):

( [N;!H0;$(NC);!$([N+]);!$(NC=,#[!#6]);!$(NC=,#[#6]);!$(N[!#6]);!$(Nc)] ) OR ( [N;!H0;$(N[N;$(N[#6]);!$(NC=,#[!#6])]);!$(NC=,#[!#6])] ) OR ( C([NH2])=[NH] ) OR ( [S;$([SH]),$([S-])] )

( [S;$(S(=O)[OH])] ) OR ( [C;$(C(=O)[OH]);!$(C(=O)([OH])[!#6])] )

( [C;$(C(=[O,N,S])[O,S]C(=[O,N,S]))] ) OR ( [C;$(C(=[O,N,S])[F,Cl,Br])] ) OR ( [C;$(C(=[O,S])=N)] ) OR ( [S;$(S(=O)[Cl,Br,F,I])] )

( [C;$(C[Br,I]);!$(C=,#[A])] ) OR ( [C;$(COS(=O)(=O))] )

( [c;$(c1([Cl,Br,F,I])nc[n,c][c,n][c,n]1)] ) OR ( [c;$(c1([F,Cl])c([N+](=O)[O-])cccc1),$(c1([F,Cl])ccc([N+](=O)[O-])cc1)] )

[c;$(c[Br,I])]

[C;$(C(=O)O);!$(C(=O)(O)[!#6]);!$(C(=O)O[!#6]);!$(C(=O)([OH]));!$(C(=O)([O-]));!$(C(=O)OC=,#[!#6])]

[C;!H0;$(C=O);!$(C(=O)[!#6]);!$(C(=O)=[A])]

Mix-n-match concept

step1

Protocol 1 Protocol 2 Protocol 3

step2

step3A step3B

step 4

step1

step2step2A step2C

step1

step 3

step 4

step 3

step 5A step 5B

new sequence new product type

products 1 products 2

products 3

step 4

step2B

Very powerful Java-based, XML drivencommand-line-enumerator - “CLE”

r7069.smk

smi

r7069.smi

r7069.1.smi

r7069.2.smi

…

r7003.smk

smi

r7069r7003.smi

r7003.1.smi

r7003.2.smi

filters/required/r7003.1

filters/exclude/r7003.1

1

1

“What should you make?”

2239

237

895

2082

6709

2083

1018

360

2424

176

2424

175

2424

177

8066

2469

6603

1838

2711

2450

2428

2429

2447

1438

2424

729

6536 824

238

258

877

868

2239

268

6534 67

4499 58

1307

7208

7210

8570 66

7198

7172

1373

346

7839

4439

34 255

2517

2423

995

1739

608

4791

6737

1306 733

2511

2512 975

4788

2268

2262

8080

2270

2263

2272

2424

731

8674

4792 470

6576

2239

194

3222

4772

6609

4783

6581

P KAP KCP R KCAP R KCA_DAGP R KCB1P R KCB1_DAGP R KCDP R KCE_DAGP R KCG_DAGP R KCH_DAGCDC2CDK1_BCDK2CDK2_ACDK2_ECDK4_D1CDK4_D2CDK5CDK5_p25CDK5_p35GSK3AGSK3BMAP K14ABLCSKGrb2_SH2FYNLCKSRCSYKZAP _70_SH2RAF1MAP 2KADKP IK4CAP P KP DKEGFREGFR_SubstrateERBB2FGFRTEKFLT1KDRP DGFRP DGFRB

Sertanty KB moleculeID

Observed Potency and Selectivity

8-9

7-8

6-7

5-6

4-5

3-4

Reported activities of top-“kinase active” molecules (excerpts)

...1 0 1 ...11 0 100

A

A A

2-4.5

R

19-24

2-4.5

2-4.519-24

19-24

R

R

D

H P4.5-7

7-10 10-14

Journal of Chemical Information and Computer Sciences, 1999, 39 (3) : 569-74

Ligand pharmacophoric potential

X TP

≅

1

Ncompounds

……

……

…...

1.…………....M105491

Ncompounds

……

……

…...

1…..Adim1

…...

Adim

1

1.…………..M10549

Reducing fingerprint dimensionality

NMDA Receptor AntagLeukotriene AntagPAF AntagAngiotensin II Blocker Ca Channel Blocker K Channel Activator Substance P AntagACAT Inhibitor Cyclooxygenase InhibLipoxygenase Inhib

Journal of Chemical Information and Computer Sciences. 2000, 40 (1): 117-125.

Target classification using ligand pharmacophoric feature(MDDR9104 - 10 largest classes)

eScreen N ObsMin ObsMax ObsAvg ObsSD PredMin PredMax PredAvg PredSD q2

ABL 170 3.77 9.10 5.85 1.16 3.77 9.11 5.87 0.99 0.85 ADK 225 5.00 10.46 7.65 1.12 5.36 9.99 7.65 0.95 0.85 CDC2 119 3.82 8.40 5.88 0.95 4.08 8.03 5.88 0.78 0.80 CDK1_B 764 3.74 8.30 6.09 0.89 3.96 7.97 6.10 0.79 0.87 CDK2 105 3.71 8.28 6.19 1.15 4.20 8.54 6.20 0.87 0.76 CDK2_A 455 4.09 8.08 6.30 0.69 4.17 7.74 6.31 0.60 0.83 CDK2_E 623 4.39 8.07 6.50 0.70 4.57 7.83 6.50 0.61 0.85 CDK4_D1 656 3.82 9.00 6.19 0.87 3.86 8.83 6.21 0.79 0.87 CDK4_D2 33 3.82 8.80 5.99 1.55 3.51 8.70 5.98 1.40 0.94 CDK5 474 3.80 8.21 6.62 0.93 3.90 8.75 6.63 0.84 0.89 CDK5_p25 417 4.00 8.15 6.78 0.75 4.67 8.14 6.79 0.66 0.83 CDK5_p35 24 4.40 7.70 5.82 0.87 4.35 6.61 5.80 0.61 0.73 CSK 439 3.87 9.00 6.36 1.09 3.27 8.84 6.39 0.94 0.84 EGFR 932 3.80 10.47 6.85 1.35 3.83 10.13 6.87 1.21 0.88 EGFR_Substrate 27 4.22 6.43 5.61 0.58 4.48 6.04 5.61 0.51 0.83 ERBB2 189 3.92 9.00 6.63 1.39 3.67 8.78 6.64 1.30 0.93 FGFR 368 4.19 8.70 5.90 0.92 4.31 7.62 5.91 0.80 0.85 FLT1 103 4.59 8.52 6.37 0.59 5.17 8.07 6.37 0.47 0.76 FYN 30 4.08 8.30 5.71 1.17 4.24 7.09 5.69 0.97 0.83 Grb2_SH2 34 4.17 8.70 6.48 1.26 4.21 8.42 6.51 1.01 0.94 GSK3A 77 5.64 8.40 7.02 0.59 6.26 8.15 7.00 0.48 0.89 GSK3B 243 3.89 8.55 6.03 0.92 4.56 8.13 6.04 0.81 0.86 KDR 281 3.94 9.00 6.39 1.05 3.96 8.69 6.41 0.90 0.82 LCK 199 3.75 9.40 6.02 1.25 3.86 8.58 6.03 1.09 0.85 MAP2K 195 5.32 8.96 6.80 0.75 5.31 8.19 6.80 0.61 0.72 MAPK14 485 4.07 9.96 6.56 0.95 4.46 9.58 6.58 0.83 0.84 PDGFR 65 4.19 8.00 5.79 0.99 4.49 7.65 5.82 0.77 0.83 PDGFRB 390 4.03 7.51 5.78 0.68 4.38 7.32 5.79 0.53 0.74 PDK 59 3.82 8.48 5.69 1.28 4.14 7.92 5.74 1.06 0.80 PIK4CA 51 3.70 7.15 4.67 0.78 3.71 6.73 4.68 0.69 0.88 PKA 127 3.74 7.59 5.20 0.88 3.86 7.06 5.21 0.76 0.82 PKC 372 3.80 8.62 6.32 1.15 3.86 8.65 6.33 1.02 0.89 PPK 33 4.00 8.52 7.18 1.00 4.46 8.29 7.20 0.84 0.87 PRKCA 163 3.93 8.55 5.82 0.99 4.13 8.28 5.82 0.80 0.83 PRKCA_DAG 106 4.01 8.00 6.00 0.90 4.25 7.84 6.02 0.72 0.73 PRKCB1 134 3.92 8.70 6.88 1.13 3.68 8.21 6.90 1.01 0.90 PRKCB1_DAG 114 3.91 8.55 6.35 1.07 4.67 8.37 6.37 0.78 0.74 PRKCD 33 4.41 8.30 6.12 1.22 4.54 7.66 6.15 1.09 0.89 PRKCE_DAG 104 4.01 8.00 5.83 0.90 4.13 7.92 5.85 0.64 0.74 PRKCG_DAG 71 5.14 8.30 6.54 0.88 5.18 7.89 6.58 0.64 0.76 PRKCH_DAG 72 4.46 8.70 7.32 0.96 5.42 8.70 7.37 0.70 0.72 RAF1 78 4.01 8.40 5.84 1.04 4.58 8.15 5.83 0.89 0.75 SRC 210 3.72 9.74 6.61 1.74 3.96 9.56 6.64 1.65 0.96 SYK 28 4.30 8.44 6.55 1.69 4.27 8.32 6.61 1.44 0.87 TEK 32 4.75 7.23 6.02 0.54 5.04 7.18 6.01 0.43 0.78 ZAP_70_SH2 43 4.03 6.00 5.06 0.50 4.03 5.98 5.07 0.43 0.85

2239

237

895

2082

6709

2083

1018

360

2424

176

2424

175

2424

177

8066

2469

6603

1838

2711

2450

2428

2429

2447

1438

2424

729

6536 824

238

258

877

868

2239

268

6534 67

4499 58

1307

7208

7210

8570 66

7198

7172

1373

346

7839

4439

34 255

2517

2423

995

1739

608

4791

6737

1306 733

2511

2512 975

4788

2268

2262

8080

2270

2263

2272

2424

731

8674

4792 470

6576

2239

194

3222

4772

6609

4783

6581

P KAP KCP R KCAP R KCA_DAGP R KCB1P R KCB1_DAGP R KCDP R KCE_DAGP R KCG_DAGP R KCH_DAGCDC2CDK1_BCDK2CDK2_ACDK2_ECDK4_D1CDK4_D2CDK5CDK5_p25CDK5_p35GSK3AGSK3BMAP K14ABLCSKGrb2_SH2FYNLCKSRCSYKZAP _70_SH2RAF1MAP 2KADKP IK4CAP P KP DKEGFREGFR_SubstrateERBB2FGFRTEKFLT1KDRP DGFRP DGFRB

Sertanty KB moleculeID

ePotency and eSelectivity

8-9

7-8

6-7

5-6

4-5

3-4

eScreen scores for top-“kinase active” molecules against each of the 46 eScreen targets

Working towards “what you should make?”eTarget correlation using the top-5 most bioactive molecules for each target

(#mols:201, #eScreen-targets: 46)

ChIP – Simulation-3

• Start with ~ 40 generic reactions with “introspective” filters

• Generate virtual protocols by graph traversal algorithm based oncompatibility of generic representations

• Enumerate virtual protocols using commercially available starting materials as input

• Eliminate structures that overlap with LUCIA Knowledgebase (KB)

• Apply Lipinski and structural filters (> 90)• MWT, HBA/HBD, ClogP, TPSA, rotBond• reactive functionalities like alkylators / acylators, electrophiles,

nucleophiles, etc. • Undesired motifs (non-standard elements, >2 halo or >1 nitro

per aryl, thioesters / ureas, un-branched chains, etc.

Ø Excerpted set: 28K novel compounds

Simulation Results (sim-3)

Compound Novelty (ChIP sim-3 excerpt)

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1Maximal compound similarity

Fre

qu

ency

KB "BioMol" (23K)MDDR (v2202.2) (65K)ACD (v2003.1) (45K)KB "BioMol+commercial" (850K)

N

NN

N

FF

NNN N

F FN

O

NN

O

N

NN

NNN N

N N N

NN

NNO N N

N N NN

N

NO

N

NN

NN

N

N

NN

NO

N

N

2270249 eABL: 7.96; eSRC: 6.83

2269216 eABL: 7.75; eSRC: 6.82

2280014 eABL: 7.36; eSRC: 7.12

2357124 eABL: 7.51; eSRC: 6.99

2267424 : eABL: 7.04; eSRC: 4.94

Excerpted ePotency & eSelectivity (sim3)

NCl

R

NO2 NH

R R NN

R

R

R

NO2

N

N

Cl

R

NN

R

R

R

NO2NN

R

R

R

NH2

NN

R

R

R

NH2

NN

R

R

R

NH

N

N

R

+

+

Excerpted generated strategies (sim3)

NH

N

OH

N

NN

N

N

N N

H

NH

N

OH

N

NN

N

NN

H

NH

N

NH

N

NN

N

ON

N

H

N

N

NH

NH

O NH

N

N N

N

Protocol-7011,7036,7005 (similar rxn sequence):

Protocol-7006,7036,7005 and Protocol-7007,7036,7005

[F,Cl]

NO2R

NH

R R N

R

R

NO2R

N

N

Cl

R

N

R

R

NO2R

N

R

R

NH2R

N

R

R

NH2R

N

R

R

NH

N

N

R

R

+

+

N

N

N

NN

N

O

N N

N

H

H

H

NS

N

N

NN

NNH

N

NH

H

N

N

NH

N

NH

NN

N

N

NN

N

N

N

S

N

N

N

NH

N

NNH

N

N

N

NNH

NNH

N

N

N

N

NN

O

NN N

N

H

N

N

Cl

N

NH

N

OH

N

NN

• More detailed scope of reaction and reaction compatibility

• More efficient survey of vProtocol space

vProtocol space is enormous:

e.g. 40 basis-set rxns ~105 million possibilities!

• Additional ePotency, eSelectivity and eADMEtox eScreens

• Partnership experimental validation

ChIP – next steps

∑hMaxRxnDept

ii

^tRxnsNumBasisSe

Leveraging GA strategies

“makelists” – A utility which generates sublists for each reactant in reaction basis-set, screening sets of commercially available molecules (e.g. ACD) through reaction-specific, “required,” “exclude,” and “introspective” filters.

“makeprimers” – A utility which builds a list of reactions that can act as primers - i.e. Reactions with sets of pre-filtered, commercially available starting materials for every reactant.

“makegene” – A utility which randomly selects from a “biased” list of named basis-set reaction smirks and generates N variable length "genes.“ A gene describes a vProtocol (e.g. r7069r7003r7036). All genes must start with primer reactions.

“evalgene” – A user-tailored, genetic algorithm called function which accepts a vProtocol-gene, enumerates and evaluates its “viability” (e.g. GA cost):

- Genes too small or too long have maximal cost

- Genes failing to enumerate final product molecules have maximal cost

- Product molecules passing post-enumeration filters (e.g. highly reactive, undesired motifs, etc) and Lipinski filters are scored with eScreens (e.g. ePotency, eSelectivity, eADMETox, etc.), novelty assessments, etc..

- Gene cost highly extensible.

N: 20 AVG: 7.12 SD: 0.82 MIN: 5.05 MAX: 8.20

1: 8.20 Cc1c(N)cccc1c2nc3nc(Nc4ncnc5c(csc45)c6ccc(Br)cc6)ncc3[nH]2

PCN: 3.(2.(MFCD04973922,1.(MFCD00127953,MFCD00082564)))

2: 8.15 Cl.Cl.Cc1c(N)cccc1c2nc3cc(Nc4ncnc5n(cc(c6ccccc6)c45)c7ccc(Br)cc7)ccc3[nH]2


3: 8.07 Cl.Cl.Cc1c(N)cccc1c2nc3cc(Nc4ncnc5c(csc45)c6ccc(Br)cc6)ccc3[nH]2


…

Sim-4d (GA excerpt)

r7069r7003r7036 -23.019

r7069r7005r7049 -17.958

r7003r7049r7036 -16.915

r7069r7005r7049r7069 -13.648

r7003r7036r7002 -10.198

r7005r7049r7036 -8.476

r7006r7069r7005 -4.165

r7002r7003r7049 -3.689

Notes: bblockSample: 20eScreenSample: 20MinDepth: 3MaxDepth: 5Lipinski: mwt [250,750]charge [-2,2]Rotbonds [0,8]HBA [0,5]HBD [0,7]

PostEnum filters: 90Score = 100-15*Max(eABL)

N

N N

N

N

H

H

H

H

HHOO

N+

O

ONNN

N NH

N+

OO

HH

Cl

N

N

S

Br

NNN

NN

S

BrN N

H

N+

OO

HNNNN

NN

S

BrN N

H

HH

H

+

r7069

r7003

r7036

MFCD00127953

MFCD04973922

MFCD00082564

N

N N

N

N

H

H

H

H

HHO

O

NOH

N

N NH

NN NO

HH H

O

O

N Cl

N

FFF

O

O

N N

N NH

NN NO

N

FF F

H H

O

Cl

O

O

N

N

FF F

N

O

N NH

NN

NO H

NN

N

N

HH

HH

O

NN

N

N

NNH

N

FFF

N NH

NN NO H

+r7069

r7005

r7049

r7069

MFCD03410215MFCD00127953

MFCD00068146

MFCD03424715

MFCD00127862

r7069r7005r7049r7069 eABL: 7.41 N: 20 AVG: 6.58 SD: 0.67 MIN: 5.37 MAX: 7.58

Sim-4d (GA excerpt)

ChIP strategic partnership program

• Early collaborative validation of the technology

• Participation in experimental and early proof of concept studies

• “Personalized” ChIP – developed around proprietary chemistries of collaborator

• Early access to ChIP technology

• Access to current LUCIA system (ChIP precursor)

Acknowledgements

Special Thanks:

National Institute of Standards and Technology (ATP program)

Steven Muskal, Ph.D.Chief Technology [email protected]

Sertanty, Inc.; 1735 N. First Street, Suite 102San Jose, CA 95112p: (760) 535-2885www.sertanty.com

Stephan Schurer

Prashant Tyagi

Sertanty’s development team

Speaker contact information:

Supplemental Slides

Reaction chemistry and SAR archive

• >10,000 HTS reactions with experimental procedures (>1,500 associated with heterocyclic Kinase inhibitors)

• >7,500 Assay protocols with detailed information

• >45 Kinase target SAR training sets

• >45 Predictive eScreenTM models

>90,000 SAR data points

>4 Million unique structures

>300,000 Unique kinase molecules

eHIA revisited

Observed v. Predicted HIA (WPSA, QPlogPow, QPlogS,BIPCaco)

00.10.20.30.40.50.60.70.80.9

1

0 0.2 0.4 0.6 0.8 1

% cHIA (/100)

% O

bse

rved

HIA

(/1

00)

CV (n=8; corr=0.86;ad=0.12)

Pred (m=11;corr=0.97;ad=0.06)

Train (o=67;corr=0.94;ad=0.07)

Observed and predicted human intestinal absorption using a newly developed neural network model. Data set published in (J. Chem. Inf. Comput. Sci. 1998, 38, 726-735) was used to generate a new, more computationally efficient model.

The GA-derived computational descriptors:

WPSA - The weakly polar component of the SASA* (halogens, P, and S)QPlogPow - The predicted log of the octanol/water partition coefficientQPlogS - The predicted aqueous solubility, log S. S in moles/liter is the concentration of the solute in a saturated solution in equilibrium with the crystalline solid.BIPCaco - The predicted apparent Caco-2 cell permeability in nm/sec -Boehringer-Ingelheim scale.

-3

-2

-1

0

1

2

3

4

5

6

-1 0 1 2 3 4 5

Predicted pLD50

Rep

orte

d pL

D50

A leave-one-out toxicity prediction performance simulation using the RefSim algorithm. 13645 examples of Oral, rat LD50 data, extracted from the Registry of Toxic Effects of Chemical Substances (RTECS), were considered in a leave-one-out simulation using the “RefSim” algorithm. Journal of Chemical Information and Computer Sciences. 2003 Sep-Oct; 43(5): 1673-8

eTox by RefSim

Mutagenicity Prediction by RefSim

4

66

3

8

0

10

20

30

40

50

60

70

-1 0 1 NoPred

Pred-Observed

Freq

uenc

y

Data From:Handbook of Carcinogenic Potency and Genotoxicity Databases (Lois Swirsky, Gold and Errol Ziegler, Eds.), CRC Press, 1997, pp. 694-724Data Files contain the experimental mutagenicity data in 1 or 0's. 742 Reference set examples; 81 Test set examples; Refsim cutoff: 0.5One indicates a mutagen and zero indicates that the compound has no mutagenic effect on Salmonella typhimurium bacteria (AMES test).

eMutagenicity by RefSim

Sertanty Inc.

Roy ThieleRoy Thiele--SardiSardiññaaChairman

Steve Muskal, Ph.D.Steve Muskal, Ph.D.Chief Technology Officer

Hung T. Tran Hung T. Tran Chief Financial Officer

Kristina Kristina KurzKurz, Ph.D., Ph.D.Director, Business Development

MDL, Affymax / Glaxo, Libraria Inc.

Thieme Publishing, Libraria Inc.

Murdock & Associates, Healthtrac Inc. Tiburon Inc., Acterna, Tektronix, Libraria Inc.

Tasmania, Brocade, Sun Microsystems

a systems approach to prioritizing the synthesis of new … · 2014. 12. 2. · compounds,...

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