<i>DSX</i>: A Knowledge-Based Scoring Function for the Assessment of Protein–Ligand Complexes

Neudert, Gerd; Klebe, G.

doi:10.1021/ci200274q

Cited by 262 publications

(242 citation statements)

References 59 publications

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“…Implementation of an interface between the server @TOME-2 and the docking program PLANTS (41) allowed virtual screening of bisphenols with the complexes described earlier used as anchoring models. Binding affinities were evaluated by using several scoring functions, including the recently developed DSX (42).…”

Section: Resultsmentioning

confidence: 99%

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

Delfosse

Grimaldi

Pons

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

331

268

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Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) α and β differ from that used by 17β-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17β-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor γ and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.crystal structure | endocrine disruptor | nuclear receptor | virtual screening

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Section: Resultsmentioning

confidence: 99%

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

Delfosse

Grimaldi

Pons

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

331

268

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“…In fact, inaccuracies in the Sybyl atom types have previously been discussed. 42 For instance, the O.3 atom type definition could be divided in at least 2 atom types as it accounts for both hydroxyl and ether groups. Such a separation is chemically meaningful as only hydroxyls can act as H-bond donors.…”

Section: ■ Discussionmentioning

confidence: 99%

FlexAID: Revisiting Docking on Non-Native-Complex Structures

Gaudreault

Najmanovich

2015

J. Chem. Inf. Model.

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Small-molecule protein docking is an essential tool in drug design and to understand molecular recognition. In the present work we introduce FlexAID, a small-molecule docking algorithm that accounts for target side-chain flexibility and utilizes a soft scoring function, i.e. one that is not highly dependent on specific geometric criteria, based on surface complementarity. The pairwise energy parameters were derived from a large dataset of true positive poses and negative decoys from the PDBbind database through an iterative process using Monte Carlo simulations. The prediction of binding poses is tested using the widely used Astex dataset as well as the HAP2 dataset, while performance in virtual screening is evaluated using a subset of the DUD dataset. We compare FlexAID to AutoDock Vina, FlexX, and rDock in an extensive number of scenarios to understand the strengths and limitations of the different programs as well as to reported results for Glide, GOLD, and DOCK6 where applicable. The most relevant among these scenarios is that of docking on flexible non-native-complex structures where as is the case in reality, the target conformation in the bound form is not known a priori. We demonstrate that FlexAID, unlike other programs, is robust against increasing structural variability. FlexAID obtains equivalent sampling success as GOLD and performs better than AutoDock Vina or FlexX in all scenarios against non-native-complex structures. FlexAID is better than rDock when there is at least one critical side-chain movement required upon ligand binding. In virtual screening, FlexAID results are lower on average than those of AutoDock Vina and rDock. The higher accuracy in flexible targets where critical movements are required, intuitive PyMOL-integrated graphical user interface and free source code as well as precompiled executables for Windows, Linux, and Mac OS make FlexAID a welcome addition to the arsenal of existing small-molecule protein docking methods.

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“…The binding mode was scored using the London Free Energy scoring function for prediction of affinity and rescored using the DrugScoreX scoring function for analysis of the complementarity and clashes between the ligand and the receptor atoms (23).…”

Section: Modeling Of the Androgen Receptor Ligand Interactionmentioning

confidence: 99%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

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DSX: A Knowledge-Based Scoring Function for the Assessment of Protein–Ligand Complexes

Cited by 262 publications

References 59 publications

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

FlexAID: Revisiting Docking on Non-Native-Complex Structures

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

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