Side-chain rotamer changes upon ligand binding: common, crucial, correlate with entropy and rearrange hydrogen bonding

Gaudreault, Francis; Chartier, Matthieu; Najmanovich, Rafaël

doi:10.1093/bioinformatics/bts395

Cited by 70 publications

(91 citation statements)

References 29 publications

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“…Such a scenario is somewhat artificial but would be representative of the approximately 10% of binding-sites that do not undergo side-chain conformational changes upon ligand binding. 7 The performance of FlexAID (66.7%) is closest to the performance of FlexX (78.8%) when docking in native structures ( Figure 4A). AutoDock Vina and rDock achieve higher success rates with 81.8% and 89.4%, respectively, in this specific scenario where side-chain flexibility is not required.…”

Section: Journal Of Chemical Information and Modelingmentioning

confidence: 85%

“…We recently quantified the minimal rotation hypothesis and observed that it is valid in approximately 20% of cases. 7 In about 90% of binding-sites, at least one side-chain rotamer change is observed in the bound complex; 7 and in 30% of these cases, side-chain movements are essential as severe steric clashes are observed in the holo form were it to retain the apoform side-chain conformations. In the present study, we introduce the molecular docking algorithm FlexAID that uses a scoring function based on surface complementarity.…”

Section: ■ Introductionmentioning

confidence: 99%

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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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Section: Journal Of Chemical Information and Modelingmentioning

confidence: 85%

Section: ■ Introductionmentioning

confidence: 99%

FlexAID: Revisiting Docking on Non-Native-Complex Structures

Gaudreault

Najmanovich

2015

J. Chem. Inf. Model.

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“…Histidine shows two side chain dihedral angles (x1 and x2) that were previously reported to be capable of very limited conformational change upon ligand binding; conversely, glutamine is described as the third most flexible side chain residue (Gaudreault et al, 2012). Hence, we speculated that the differential inherent flexibility of these two residues might result in altered flexibility in the sugar binding pocket.…”

Section: Ugt8 Galactosidates Bile Acidsmentioning

confidence: 86%

A Novel Function for UDP Glycosyltransferase 8: Galactosidation of Bile Acids

et al. 2014

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The human UDP glycosyltransferase (UGT) superfamily comprises four families of enzymes that catalyze the addition of sugar residues to small lipophilic chemicals. The UGT1 and UGT2 enzymes use UDP-glucuronic acid, and UGT3 enzymes use UDP-N-acetylglucosamine, UDP-glucose, and UDP-xylose to conjugate xenobiotics, including drugs and endobiotics such as metabolic byproducts, hormones, and signaling molecules. This metabolism renders the substrate more polar and more readily excreted from the body and/or functionally inactive. The fourth UGT family, called UGT8, contains only one member that, unlike other UGTs, is considered biosynthetic. UGT8 uses UDP galactose to galactosidate ceramide, a key step in the synthesis of brain sphingolipids. To date other substrates for this UGT have not been identified and there has been no suggestion that UGT8 is involved in metabolism of endo-or xenobiotics. We reexamined the functions of UGT8 and discovered that it efficiently galactosidates bile acids and drug-like bile acid analogs. UGT8 conjugates bile acids ∼60-fold more efficiently than ceramide based on in vitro assays with substrate preference deoxycholic acid . chenodeoxycholic acid . cholic acid . hyodeoxycholic acid . ursodeoxycholic acid. Activities of human and mouse UGT8 are qualitatively similar. UGT8 is expressed at significant levels in kidney and gastrointestinal tract (intestine, colon) where conjugation of bile acids is likely to be metabolically significant. We also investigate the structural determinants of UDP-galactose selectivity. Our novel findings suggest a new role for UGT8 as a modulator of bile acid homeostasis and signaling.

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“…For example, side-chain rotamer changes upon ligand binding occur in 90% of cases. 52 Flexibility is often related to function and …”

Section: Journal Of Chemical Information and Modelingmentioning

confidence: 99%

Detection of Binding Site Molecular Interaction Field Similarities

Chartier

Najmanovich

2015

J. Chem. Inf. Model.

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Protein binding-site similarity detection methods can be used to predict protein function and understand molecular recognition, as a tool in drug design for drug repurposing and polypharmacology, and for the prediction of the molecular determinants of drug toxicity. Here, we present IsoMIF, a method able to identify binding site molecular interaction field similarities across protein families. IsoMIF utilizes six chemical probes and the detection of subgraph isomorphisms to identify geometrically and chemically equivalent sections of protein cavity pairs. The method is validated using six distinct data sets, four of those previously used in the validation of other methods. The mean area under the receiver operator curve (AUC) obtained across data sets for IsoMIF is higher than those of other methods. Furthermore, while IsoMIF obtains consistently high AUC values across data sets, other methods perform more erratically across data sets. IsoMIF can be used to predict function from structure, to detect potential cross-reactivity or polypharmacology targets, and to help suggest bioisosteric replacements to known binding molecules. Given that IsoMIF detects spatial patterns of molecular interaction field similarities, its predictions are directly related to pharmacophores and may be readily translated into modeling decisions in structure-based drug design. IsoMIF may in principle detect similar binding sites with distinct amino acid arrangements that lead to equivalent interactions within the cavity. The source code to calculate and visualize MIFs and MIF similarities are freely available.

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Side-chain rotamer changes upon ligand binding: common, crucial, correlate with entropy and rearrange hydrogen bonding

Cited by 70 publications

References 29 publications

FlexAID: Revisiting Docking on Non-Native-Complex Structures

FlexAID: Revisiting Docking on Non-Native-Complex Structures

A Novel Function for UDP Glycosyltransferase 8: Galactosidation of Bile Acids

Detection of Binding Site Molecular Interaction Field Similarities

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