rdkit.Chem.BRICS

1 # $Id: BRICS.py 1005 2009-03-04 16:28:31Z glandrum $ 2 # 3 # Copyright (c) 2009, Novartis Institutes for BioMedical Research Inc. 4 # All rights reserved. 5 # 6 # Redistribution and use in source and binary forms, with or without 7 # modification, are permitted provided that the following conditions are 8 # met: 9 # 10 # * Redistributions of source code must retain the above copyright 11 # notice, this list of conditions and the following disclaimer. 12 # * Redistributions in binary form must reproduce the above 13 # copyright notice, this list of conditions and the following 14 # disclaimer in the documentation and/or other materials provided 15 # with the distribution. 16 # * Neither the name of Novartis Institutes for BioMedical Research Inc. 17 # nor the names of its contributors may be used to endorse or promote 18 # products derived from this software without specific prior written permission. 19 # 20 # THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS 21 # "AS IS" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT 22 # LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR 23 # A PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT 24 # OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, 25 # SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT 26 # LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, 27 # DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY 28 # THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT 29 # (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE 30 # OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. 31 # 32 # Created by Greg Landrum, Nov 2008 33 34 """ Implementation of the BRICS algorithm from Degen et al. ChemMedChem *3* 1503-7 (2008) 35 36 """ 37 from rdkit import Chem 38 from rdkit.Chem import rdChemReactions as Reactions 39 import sys,re 40 41 # These are the definitions that will be applied to fragment molecules: 42 environs = { 43 'L1':('[#6:1,#7,#8,#0][C:2](=[O:3])','[*:1][C:2](=[O:3])-[1*]'), 44 'L2':('[N:21;!$(N=*)]-;!@[#6:22,#0]','[2*]-[N:21][*:22]'), 45 'L3':('[O:31]-;!@[#6:32]','[3*]-[O:31][*:32]'), 46 'L4':('[#6:41]-;!@[C:42;!$(C=*)]','[*:41]-[C:42]-[4*]'), 47 'L5':('[N:51;!$(N*!-*);!$(N=*);!$(N-[!C])]-[C:52]','[5*]-[N:51][*:52]'), 48 'L6':('[C:61](=[O:62])-;!@[#6:63,#7,#8]','[6*]-[C:61](=[O:62])[*:63]'), 49 'L7a':('[#6:71]-;!@[C:72]','[#6:71]-;!@[C:72]=[7*]'), 50 'L7b':('[C:74]-;!@[#6:73]','[#6:73]-;!@[C:74]=[7*]'), 51 'L8':('[C:81]-;!@[C:82]-;!@[#6:83]','[8*]-[C:81]-;!@[C:82]-;!@[*:83]'), 52 'L9':('[n:91;$(n(:[c,n,o,s]):[c,n,o,s])]','[9*]-[*:91]'), 53 'L10':('[N:101;R;$(N(@C(=O))@[C,N,O,S])]','[10*]-[N:101]'), 54 'L11':('[S:112](-;!@[#6:111])','[*:111][S:112]-[11*]'), 55 'L12':('[#6:121][S:122](=[O:123])(=[O:124])','[*:121][S:122](=[O:123])(=[O:124])-[12*]'), 56 'L13':('[C:131;$(C(-;@[C,N,O,S])-;@[N,O,S])]','[*:131]-[13*]'), 57 'L14':('[c:141;$(c(:[c,n,o,s]):[n,o,s])]','[*:141]-[14*]'), 58 'L14b':('[c:142;$(c(:[c,n,o,s]):[n,o,s])]','[*:142]-[14*]'), 59 'L15':('[C:151;$(C(-;@C)-;@C)]','[*:151]-[15*]'), 60 'L16':('[c:161;$(c(:c):c)]','[*:161]-[16*]'), 61 'L16b':('[c:162;$(c(:c):c)]','[*:162]-[16*]'), 62 63 } 64 reactionDefs = ( 65 # L1 66 [ 67 "{L1}-;!@{L3}>>{L1p}.{L3p}", 68 "{L1}-;!@{L2}>>{L1p}.{L2p}", 69 "{L1}-;!@{L10}>>{L1p}.{L10p}", 70 ], 71 72 # L2 73 [ 74 "{L12}-;!@{L2}>>{L12p}.{L2p}", 75 "{L14}-;!@{L2}>>{L14p}.{L2p}", 76 "{L16}-;!@{L2}>>{L16p}.{L2p}", 77 ], 78 79 # L3 80 [ 81 "{L4}-;!@{L3}>>{L4p}.{L3p}", 82 "{L13}-;!@{L3}>>{L13p}.{L3p}", 83 "{L14}-;!@{L3}>>{L14p}.{L3p}", 84 "{L15}-;!@{L3}>>{L15p}.{L3p}", 85 "{L16}-;!@{L3}>>{L16p}.{L3p}", 86 ], 87 88 # L4 89 [ 90 "{L4}-;!@{L5}>>{L4p}.{L5p}", 91 "{L4}-;!@{L3}>>{L4p}.{L3p}", 92 "{L4}-;!@{L11}>>{L4p}.{L11p}", 93 ], 94 95 # L5 96 [ 97 "{L13}-;!@{L5}>>{L13p}.{L5p}", 98 "{L15}-;!@{L5}>>{L15p}.{L5p}", 99 ], 100 101 # L6 102 [ 103 "{L13}-;!@{L6}>>{L13p}.{L6p}", 104 "{L14}-;!@{L6}>>{L14p}.{L6p}", 105 "{L15}-;!@{L6}>>{L15p}.{L6p}", 106 "{L16}-;!@{L6}>>{L16p}.{L6p}", 107 ], 108 109 # L7 110 [ 111 "{L7a}=;!@{L7b}>>{L7ap}.{L7bp}", 112 ], 113 114 # L8 115 [ 116 "{L9}-;!@{L8}>>{L9p}.{L8p}", 117 "{L10}-;!@{L8}>>{L10p}.{L8p}", 118 "{L13}-;!@{L8}>>{L13p}.{L8p}", 119 "{L14}-;!@{L8}>>{L14p}.{L8p}", 120 "{L15}-;!@{L8}>>{L15p}.{L8p}", 121 "{L16}-;!@{L8}>>{L16p}.{L8p}", 122 ], 123 124 # L9 125 [ 126 "{L9}-;!@{L15}>>{L9p}.{L15p}", 127 "{L9}-;!@{L16}>>{L9p}.{L16p}", 128 ], 129 130 # L10 131 [ 132 "{L10}-;!@{L13}>>{L10p}.{L13p}", 133 "{L10}-;!@{L14}>>{L10p}.{L14p}", 134 "{L10}-;!@{L15}>>{L10p}.{L15p}", 135 "{L10}-;!@{L16}>>{L10p}.{L16p}", 136 ], 137 138 # L11 139 [ 140 "{L11}-;!@{L13}>>{L11p}.{L13p}", 141 "{L11}-;!@{L14}>>{L11p}.{L14p}", 142 "{L11}-;!@{L15}>>{L11p}.{L15p}", 143 "{L11}-;!@{L16}>>{L11p}.{L16p}", 144 ], 145 146 # L12 147 # none left 148 149 # L13 150 [ 151 "{L13}-;!@{L14}>>{L13p}.{L14p}", 152 "{L13}-;!@{L15}>>{L13p}.{L15p}", 153 "{L13}-;!@{L16}>>{L13p}.{L16p}", 154 ], 155 156 # L14 157 [ 158 "{L14}-;!@{L14b}>>{L14p}.{L14bp}", # not in original paper 159 "{L14}-;!@{L15}>>{L14p}.{L15p}", 160 "{L14}-;!@{L16}>>{L14p}.{L16p}", 161 ], 162 163 # L15 164 [ 165 "{L15}-;!@{L16}>>{L15p}.{L16p}", 166 ], 167 168 # L16 169 [ 170 "{L16}-;!@{L16b}>>{L16p}.{L16bp}", # not in original paper 171 ], 172 ) 173 174 smartsGps=reactionDefs 175 for k,v in environs.iteritems(): 176 for gp in smartsGps: 177 for j,sma in enumerate(gp): 178 sma = sma.replace('{%sp}'%k,v[1]).replace('{%s}'%k,v[0]) 179 gp[j] =sma 180 for gp in smartsGps: 181 for defn in gp: 182 try: 183 Reactions.ReactionFromSmarts(defn) 184 except: 185 print defn 186 raise 187 188 reactions = tuple([[Reactions.ReactionFromSmarts(y) for y in x] for x in smartsGps]) 189 reverseReactions = [] 190 for i,rxnSet in enumerate(smartsGps): 191 for j,sma in enumerate(rxnSet): 192 rs,ps = sma.split('>>') 193 sma = '%s>>%s'%(ps,rs) 194 rxn = Reactions.ReactionFromSmarts(sma) 195 labels = re.findall(r'\[([0-9]+?)\*\]',ps) 196 rxn._matchers=[Chem.MolFromSmiles('[%s*]'%x) for x in labels] 197 reverseReactions.append(rxn)

198 -def BRICSDecompose(mol,allNodes=None,minFragmentSize=2,onlyUseReactions=None, 199 silent=True,keepNonLeafNodes=False):

200 """ returns the BRICS decomposition for a molecule """ 201 mSmi = Chem.MolToSmiles(mol,1) 202 203 if allNodes is None: 204 allNodes=set() 205 206 if mSmi in allNodes: 207 return set() 208 209 activePool={mSmi:mol} 210 allNodes.add(mSmi) 211 for gpIdx,reactionGp in enumerate(reactions): 212 newPool = {} 213 while activePool: 214 matched=False 215 nSmi = activePool.keys()[0] 216 mol = activePool.pop(nSmi) 217 for rxnIdx,reaction in enumerate(reactionGp): 218 if onlyUseReactions and (gpIdx,rxnIdx) not in onlyUseReactions: 219 continue 220 if not silent: 221 print '--------' 222 print reactionDefs[gpIdx][rxnIdx] 223 ps = reaction.RunReactants((mol,)) 224 if ps: 225 if not silent: print nSmi,'->',len(ps),'products' 226 for prodSeq in ps: 227 seqOk=True 228 # we want to disqualify small fragments, so sort the product sequence by size 229 prodSeq = [(prod.GetNumAtoms(onlyHeavy=True),prod) for prod in prodSeq] 230 prodSeq.sort() 231 for nats,prod in prodSeq: 232 pSmi = Chem.MolToSmiles(prod,1) 233 if minFragmentSize>0: 234 nDummies = pSmi.count('*') 235 if nats-nDummies<minFragmentSize: 236 seqOk=False 237 break 238 prod.pSmi = pSmi 239 if seqOk: 240 matched=True 241 for nats,prod in prodSeq: 242 pSmi = prod.pSmi 243 #print '\t',nats,pSmi 244 if pSmi not in allNodes: 245 activePool[pSmi] = prod 246 allNodes.add(pSmi) 247 if not matched: 248 newPool[nSmi]=mol 249 activePool = newPool 250 return set(activePool.keys())

251 252 253 import random 254 dummyPattern=Chem.MolFromSmiles('[*]')

255 -def BRICSBuild(fragments,onlyCompleteMols=True,seeds=None,uniquify=True, 256 scrambleReagents=True,maxDepth=3):

257 seen = set() 258 if not seeds: 259 seeds = list(fragments) 260 if scrambleReagents: 261 seeds = list(seeds) 262 random.shuffle(seeds) 263 if scrambleReagents: 264 tempReactions = list(reverseReactions) 265 random.shuffle(tempReactions) 266 else: 267 tempReactions=reverseReactions 268 for seed in seeds: 269 seedIsR1=False 270 seedIsR2=False 271 nextSteps=[] 272 for rxn in tempReactions: 273 if seed.HasSubstructMatch(rxn._matchers[0]): 274 seedIsR1=True 275 if seed.HasSubstructMatch(rxn._matchers[1]): 276 seedIsR2=True 277 for fragment in fragments: 278 ps = None 279 if fragment.HasSubstructMatch(rxn._matchers[0]): 280 if seedIsR2: 281 ps = rxn.RunReactants((fragment,seed)) 282 if fragment.HasSubstructMatch(rxn._matchers[1]): 283 if seedIsR1: 284 ps = rxn.RunReactants((seed,fragment)) 285 if ps: 286 for p in ps: 287 if uniquify: 288 pSmi =Chem.MolToSmiles(p[0],True) 289 if pSmi in seen: 290 continue 291 else: 292 seen.add(pSmi) 293 if p[0].HasSubstructMatch(dummyPattern): 294 nextSteps.append(p[0]) 295 if not onlyCompleteMols: 296 yield p[0] 297 else: 298 yield p[0] 299 if nextSteps and maxDepth>1: 300 for p in BRICSBuild(fragments,onlyCompleteMols=onlyCompleteMols, 301 seeds=nextSteps,uniquify=uniquify, 302 maxDepth=maxDepth-1): 303 if uniquify: 304 pSmi =Chem.MolToSmiles(p,True) 305 if pSmi in seen: 306 continue 307 else: 308 seen.add(pSmi) 309 yield p

310 311 312 313 # ------- ------- ------- ------- ------- ------- ------- ------- 314 # Begin testing code 315 if __name__=='__main__': 316 import unittest

317 - class TestCase(unittest.TestCase):

318 - def test1(self):

319 m = Chem.MolFromSmiles('CC(=O)OC') 320 res = BRICSDecompose(m) 321 self.failUnless(res) 322 self.failUnless(len(res)==2) 323 324 m = Chem.MolFromSmiles('CC(=O)N1CCC1=O') 325 res = BRICSDecompose(m) 326 self.failUnless(res) 327 self.failUnless(len(res)==2) 328 329 m = Chem.MolFromSmiles('c1ccccc1N(C)C') 330 res = BRICSDecompose(m) 331 self.failUnless(res) 332 self.failUnless(len(res)==2) 333 334 m = Chem.MolFromSmiles('c1cccnc1N(C)C') 335 res = BRICSDecompose(m) 336 self.failUnless(res) 337 self.failUnless(len(res)==2) 338 339 m = Chem.MolFromSmiles('o1ccnc1N(C)C') 340 res = BRICSDecompose(m) 341 self.failUnless(res) 342 self.failUnless(len(res)==2) 343 344 m = Chem.MolFromSmiles('c1ccccc1OC') 345 res = BRICSDecompose(m) 346 self.failUnless(res) 347 self.failUnless(len(res)==2) 348 349 m = Chem.MolFromSmiles('o1ccnc1OC') 350 res = BRICSDecompose(m) 351 self.failUnless(res) 352 self.failUnless(len(res)==2) 353 354 m = Chem.MolFromSmiles('O1CCNC1OC') 355 res = BRICSDecompose(m) 356 self.failUnless(res) 357 self.failUnless(len(res)==2) 358 359 m = Chem.MolFromSmiles('CCCSCC') 360 res = BRICSDecompose(m) 361 self.failUnless(res) 362 self.failUnless(len(res)==4)

363

364 - def test2(self):

365 # example from the paper, nexavar: 366 m = Chem.MolFromSmiles('CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1') 367 res = BRICSDecompose(m) 368 self.failUnless(res) 369 self.failUnless(len(res)==7,res)

370

371 - def test3(self):

372 m = Chem.MolFromSmiles('FC(F)(F)C1=C(Cl)C=CC(NC(=O)NC2=CC=CC=C2)=C1') 373 res = BRICSDecompose(m) 374 self.failUnless(res) 375 self.failUnless(len(res)==3,res)

376 377

378 - def test4(self):

379 allNodes = set() 380 m = Chem.MolFromSmiles('c1ccccc1OCCC') 381 res = BRICSDecompose(m,allNodes=allNodes) 382 self.failUnless(res) 383 leaves=res 384 self.failUnless(len(allNodes)==5,allNodes) 385 res = BRICSDecompose(m,allNodes=allNodes) 386 self.failIf(res) 387 self.failUnless(len(allNodes)==5,allNodes) 388 389 m = Chem.MolFromSmiles('c1ccccc1OCCCC') 390 res = BRICSDecompose(m,allNodes=allNodes) 391 self.failUnless(res) 392 leaves.update(res) 393 self.failUnless(len(allNodes)==8,allNodes) 394 self.failUnless(len(leaves)==6,leaves) 395 396 397 m = Chem.MolFromSmiles('c1cc(C(=O)NCC)ccc1OCCC') 398 res = BRICSDecompose(m,allNodes=allNodes) 399 self.failUnless(res) 400 leaves.update(res) 401 self.failUnless(len(allNodes)==13,allNodes) 402 self.failUnless(len(leaves)==9,leaves)

403

404 - def test5(self):

405 allNodes = set() 406 frags = [ 407 '[14*]c1ncncn1', 408 '[16*]c1ccccc1', 409 '[14*]c1ncccc1', 410 ] 411 frags = [Chem.MolFromSmiles(x) for x in frags] 412 res = BRICSBuild(frags) 413 self.failUnless(res) 414 res= list(res) 415 self.failUnless(len(res)==6) 416 smis = [Chem.MolToSmiles(x,True) for x in res] 417 self.failUnless('c1ccc(-c2ccccc2)cc1' in smis) 418 self.failUnless('c1ccc(-c2ncccc2)cc1' in smis)

419

420 - def test6(self):

421 allNodes = set() 422 frags = [ 423 '[16*]c1ccccc1', 424 '[3*]OC', 425 '[9*]n1cccc1', 426 ] 427 frags = [Chem.MolFromSmiles(x) for x in frags] 428 res = BRICSBuild(frags) 429 self.failUnless(res) 430 res= list(res) 431 self.failUnless(len(res)==3) 432 smis = [Chem.MolToSmiles(x,True) for x in res] 433 self.failUnless('c1ccc(-c2ccccc2)cc1' in smis) 434 self.failUnless('COc1ccccc1' in smis) 435 self.failUnless('c1ccc(-n2cccc2)cc1' in smis)

436

437 - def test7(self):

438 allNodes = set() 439 frags = [ 440 '[16*]c1ccccc1', 441 '[3*]OC', 442 '[3*]OCC(=O)[6*]', 443 ] 444 frags = [Chem.MolFromSmiles(x) for x in frags] 445 res = BRICSBuild(frags) 446 self.failUnless(res) 447 res= list(res) 448 smis = [Chem.MolToSmiles(x,True) for x in res] 449 self.failUnless(len(res)==3) 450 self.failUnless('c1ccc(-c2ccccc2)cc1' in smis) 451 self.failUnless('COc1ccccc1' in smis) 452 self.failUnless('O=C(COc1ccccc1)c1ccccc1' in smis)

453

454 - def test8(self):

455 random.seed(23) 456 base = Chem.MolFromSmiles("n1cncnc1OCC(C1CC1)OC1CNC1") 457 catalog = BRICSDecompose(base) 458 self.failUnless(len(catalog)==8) 459 catalog = [Chem.MolFromSmiles(x) for x in catalog] 460 ms = list(BRICSBuild(catalog)) 461 self.failUnless(len(ms)==19)

462 463 464 unittest.main() 465

Source Code for Module rdkit.Chem.BRICS