FC-Bioisostere case study

Methyl-ester / benzo[d]isoxazole case study:

Context:

The alkenyldiarylmethanes (ADAMs) are a class of potent and highly specific HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs). Unfortunately, most of the ADAMs are too unstable toward hydrolysis in blood plasma to be considered as potential therapeutic candidates. A series of alkenyldiarylmethanes (ADAMs) with a benzo[d]isoxazole ring in place of the metabolically unstable methyl ester moiety and an adjacent methoxyl group were synthesized by 1Deng et al. The authors demonstrated that the benzo[d]isoxazole ring is an effective bioisosteric replacement of the metabolically labile methyl ester moiety in ADAMs

 

Is it raised by MED-SuMo within the PDB ?

Here is a MED-SuMo 3D search (db_bioisostere profile) over the full PDB from protein structure having a Methyl-Ester in a cocrystallized ligand structure. The snapshot highlights the superposition of pockets RDA in HSP82 protein (2FXS in white) and hit N°54, the CXZ ligand of HSP90 protein (3BMY in green). Surface Chemical Features used for 3D superposition are shown (balls and ball&sticks). The dash line highlights the strong overlap between methyl ester and benzo[d]isoxazole groups.

MED-SuMo superposition of 3bmy on 2fxs

 

OK, but can extract that automatically and make it available for bioiostere replacement ?

Here is the FC-Bioisostere protocol2 we set up to explore bioisostere candidates on ADAM:

  1. DATABASE : we built a database of bioisosteric pairs by driving MED-SuMo MEDIT software from FC-Bioisostere GUI: a whole set of 5139 protein-ligand binding site queries (xrayResolution < 2,5A ; 350 < MW < 550 ; PDB_occurencies < 11 ; Sept2013) were performed toward all PDB (SuMoScore > 6 ; MaxHit = 100). From those ligand superpositions, a Database of 376096 pairs of bioisosteric fragments was generated (Fragmentor mode to deconvolute PDB ligand in fragments with a list of 281472 Pubchem fragments having 3 to 13 atoms ; FragmentCandidate > 5 Heavy/dummy Atom ; 2D filter per binding site ; 2SealScore_to_detect_overlaping_fragmen > 0,7).
  2. QUERY : we loaded a 3D model of ADAM28a3 (BindingDB_2786) as the starting point for bioisostere enumeration. This Query has been deconvoluted in 49 QuerySubstructures according to 2D matches to the bioisostere Database, only methyl ester QuerySubstructure was selected.
  3. POSSIBLE REPLACEMENT : 2D searching this methyl ester in the Database retrieved 28 possible replacements (RMSD_to_QuerySubstructure < 2A), including the methyl-ester/benzo[d]isoxazole bioisostere (as detected by MED-SuMo, see above)
  4. BIOISOSTERE ENUMERATION: 18 molecules were generated including the benzo[d]isoxazole bioisostere (see Fig. hereunder) by using the TwoWayAttachment algorithm for bioisostere recombination, and by applying filter on the fly on disconnected molecule and unusual valences

ADAM case study in FC-Bioisostere

Fig.: FC-Bioisostere on ADAM28a ; Query & QuerySubstructures on the left side ; PossibleReplacements and Bioisosteres on the middle ; 3D display in the context of 3IS9 protein on the right

 

References:

  1. Deng BL, Zhao Y, Hartman TL, Watson K, Buckheit RW Jr, Pannecouque C, De Clercq E, Cushman M,  Eur. J. Med. Chem. 2009 Mar, 44 (3), 1210–4
  2. Moriaud F, Adcock SA, Vorotyntsev A, Doppelt-Azeroual O, Richard SB and Delfaud F, ACS Symposium series1076, Chapter book 5, p71-88
  3. Liu T, Lin Y, Wen X, Jorrisen RN, Gilson MK, Nucleic Acids Res. 2007, 35, D198–D201

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