Brief. Bioinformatics - Identify drug repurposing candidates by mining the protein data bank.

Tópicos

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{ compound(1573) activ(1297) structur(1058) }
{ bind(1733) structur(1185) ligand(1036) }
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{ can(774) often(719) complex(702) }
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{ imag(2830) propos(1344) filter(1198) }
{ network(2748) neural(1063) input(814) }
{ take(945) account(800) differ(722) }
{ assess(1506) score(1403) qualiti(1306) }
{ chang(1828) time(1643) increas(1301) }
{ method(984) reconstruct(947) comput(926) }
{ studi(1410) differ(1259) use(1210) }
{ research(1085) discuss(1038) issu(1018) }
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{ signal(2180) analysi(812) frequenc(800) }
{ group(2977) signific(1463) compar(1072) }
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{ use(976) code(926) identifi(902) }
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{ implement(1333) system(1263) develop(1122) }
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{ activ(1452) weight(1219) physic(1104) }
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{ method(2212) result(1239) propos(1039) }
{ detect(2391) sensit(1101) algorithm(908) }

Resumo

Predicting off-targets by computational methods is gaining increasing interest in early-stage drug discovery. Here, we present a computational method based on full 3D comparisons of 3D structures. When a similar binding site is detected in the Protein Data Bank (PDB) (or any protein structure database), it is possible that the corresponding ligand also binds to that similar site. On one hand, this target hopping case is probably rare because it requires a high similarity between the binding sites. On the other hand, it could be a strong rational evidence to highlight possible off-target reactions and possibly a potential undesired side effect. This target-based drug repurposing can be extended a significant step further with the capability of searching the full surface of all proteins in the PDB, and therefore not relying on pocket detection. Using this approach, we describe how MED-SuMo reproduces the repurposing of tadalafil from PDE5A to PDE4A and a structure of PDE4A with tadalafil. Searching for local protein similarities generates more hits than for whole binding site similarities and therefore fragment repurposing is more likely to occur than for drug-sized compounds. In this work, we illustrate that by mining the PDB for proteins sharing similarities with the hinge region of protein kinases. The experimentally validated examples, biotin carboxylase and synapsin, are retrieved. Further to fragment repurposing, this approach can be applied to the detection of druggable sites from 3D structures. This is illustrated with detection of the protein kinase hinge motif in the HIV-RT non-nucleosidic allosteric site.

Resumo Limpo

predict offtarget comput method gain increas interest earlystag drug discoveri present comput method base full d comparison d structur similar bind site detect protein data bank pdb protein structur databas possibl correspond ligand also bind similar site one hand target hop case probabl rare requir high similar bind site hand strong ration evid highlight possibl offtarget reaction possibl potenti undesir side effect targetbas drug repurpos can extend signific step capabl search full surfac protein pdb therefor reli pocket detect use approach describ medsumo reproduc repurpos tadalafil pdea pdea structur pdea tadalafil search local protein similar generat hit whole bind site similar therefor fragment repurpos like occur drugsiz compound work illustr mine pdb protein share similar hing region protein kinas experiment valid exampl biotin carboxylas synapsin retriev fragment repurpos approach can appli detect druggabl site d structur illustr detect protein kinas hing motif hivrt nonnucleosid alloster site

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