J Chem Inf Model - CSAR scoring challenge reveals the need for new concepts in estimating protein-ligand binding affinity.

Tópicos

{ bind(1733) structur(1185) ligand(1036) }
{ studi(1119) effect(1106) posit(819) }
{ take(945) account(800) differ(722) }
{ model(2341) predict(2261) use(1141) }
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{ featur(3375) classif(2383) classifi(1994) }
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{ method(2212) result(1239) propos(1039) }
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Resumo

The dG prediction accuracy by the Lead Finder docking software on the CSAR test set was characterized by R(2)=0.62 and rmsd=1.93 kcal/mol, and the method of preparation of the full-atom structures of the test set did not significantly affect the resulting accuracy of predictions. The primary factors determining the correlation between the predicted and experimental values were the van der Waals interactions and solvation effects. Those two factors alone accounted for R(2)=0.50. The other factors that affected the accuracy of predictions, listed in the order of decreasing importance, were the change of ligand's internal energy upon binding with protein, the electrostatic interactions, and the hydrogen bonds. It appears that those latter factors contributed to the independence of the prediction results from the method of full-atom structure preparation. Then, we turned our attention to the other factors that could potentially improve the scoring function in order to raise the accuracy of the dG prediction. It turned out that the ligand-centric factors, including Mw, cLogP, PSA, etc. or protein-centric factors, such as the functional class of protein, did not improve the prediction accuracy. Following that, we explored if the weak molecular interactions such as X-H...Ar, X-H...Hal, CO...Hal, C-H...X, stacking and p-cationic interactions (where X is N or O), that are generally of interest to the medicinal chemists despite their lack of proper molecular mechanical parametrization, could improve dG prediction. Our analysis revealed that out of these new interactions only CO...Hal is statistically significant for dG predictions using Lead FInder scoring function. Accounting for the CO...Hal interaction resulted in the reduction of the rmsd from 2.19 to 0.69 kcal/mol for the corresponding structures. The other weak interaction factors were not statistically significant and therefore irrelevant to the accuracy of dG prediction. On the basis of our findings from our participation in the CSAR scoring challenge we conclude that a significant increase of accuracy predictions necessitates breakthrough scoring approaches. We anticipate that the explicit accounting for water molecules, protein flexibility, and a more thermodynamically accurate method of dG calculation rather than single point energy calculation may lead to such breakthroughs.

Resumo Limpo

dg predict accuraci lead finder dock softwar csar test set character r rmsd kcalmol method prepar fullatom structur test set signific affect result accuraci predict primari factor determin correl predict experiment valu van der waal interact solvat effect two factor alon account r factor affect accuraci predict list order decreas import chang ligand intern energi upon bind protein electrostat interact hydrogen bond appear latter factor contribut independ predict result method fullatom structur prepar turn attent factor potenti improv score function order rais accuraci dg predict turn ligandcentr factor includ mw clogp psa etc proteincentr factor function class protein improv predict accuraci follow explor weak molecular interact xhar xhhal cohal chx stack pcation interact x n o general interest medicin chemist despit lack proper molecular mechan parametr improv dg predict analysi reveal new interact cohal statist signific dg predict use lead finder score function account cohal interact result reduct rmsd kcalmol correspond structur weak interact factor statist signific therefor irrelev accuraci dg predict basi find particip csar score challeng conclud signific increas accuraci predict necessit breakthrough score approach anticip explicit account water molecul protein flexibl thermodynam accur method dg calcul rather singl point energi calcul may lead breakthrough

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