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Implementation of PLS discriminant analysis to rank indirubin derivatives against decoys

100%

Crisan L., Pacureanu L., Avram S., Bora A., Kurunczi L.

Open Chemistry

2013

vol. 11

issue 10

1644-1656

Partial Least Squares Discriminant Analysis (PLS-DA) is employed to obtain novel combinations of energetic terms present in classical scoring functions, which exceed and compensates the “traditional” consensus scheme. These novel scoring functions were involved to rank the database of indirubin inhibitors of glycogen synthase kinase-3β and cyclin dependent kinase-2 decoys from Directory of Useful Decoys. The ability of docking-scoring algorithm to prioritize the actives is assessed by means of several metrics. The best classification function includes donor component of Chemgauss2, steric contribution from Chemgauss3 and rotatable bond term of ScreenScore and provide significant improvement of enrichment factor at 5% of database. [...]

QSAR study and molecular docking on indirubin inhibitors of Glycogen Synthase Kinase-3

86%

Crisan L., Pacureanu L., Bora A., Avram S., Kurunczi L., Simon Z.

Open Chemistry

2013

vol. 11

issue 1

63-77

The current study describes the development of in silico models based on a novel alternative of the MTD-PLS methodology (Partial-Least-Squares variant of Minimal Topologic Difference) developed by our group to predict the inhibition of GSK-3β by indirubin derivatives. The new MTD-PLS methodology involves selection rules for the PLS equation coefficients based on physico-chemical considerations aimed at reducing the bias in the output information. These QSAR models have been derived using calculated fragmental descriptors relevant to binding including polarizability, hydrophobicity, hydrogen bond donor, hydrogen bond acceptor, volume and electronic effects. The MTD-PLS methodology afforded moderate but robust statistical characteristics (R2 Y(CUM) = 0.707, Q2(CUM) = 0.664). The MTD-PLS model obtained has been validated in terms of predictive ability by joined internal-external cross-validation applying Golbraikh-Tropsha criteria and Y-randomization test. The information supplied by the MTD-PLS model has been evaluated against Fujita-Ban outcomes that afforded a statistically reliable model (R2=0.923). Furthermore, the results originated from QSAR models were laterally validated with docking insights that suggested the substitution pattern for the design of new indirubins with improved pharmacological potential against GSK-3β. The new restriction rules introduced in this paper are applicable and provide reliable results in accordance with physico-chemical reality.

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2 Open Chemistry

2 2013

2 Avram S.

2 Bora A.

2 Crisan L.

2 Kurunczi L.

2 Pacureanu L.

1 Simon Z.

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Implementation of PLS discriminant analysis to rank indirubin derivatives against decoys

QSAR study and molecular docking on indirubin inhibitors of Glycogen Synthase Kinase-3