Extra Precision Glide:  Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand Complexes

Friesner, Richard A.; Murphy, Ryan O.; Repasky, Matthew P.; Frye, Leah L.; Greenwood, Jeremy R.; Halgren, Thomas A.; Sanschagrin, Paul C.; Mainz, Daniel T.

doi:10.1021/jm051256o

Cited by 5,619 publications

(4,455 citation statements)

References 40 publications

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“…This so-called hydrophobic enclosure of the adenine binding site enhances the hydrogen bonding interactions to the hinge region. 28 Residues 181 and 974, which form the top and bottom of the adenine binding site, are highly conserved. The conservation is probably a result of steric constraints: Larger hydrophobic residues would prevent ATP from binding.…”

Section: Discussionmentioning

confidence: 99%

An enriched structural kinase database to enable kinome‐wide structure‐based analyses and drug discovery

et al. 2010

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The development of a kinase structural database, the kinase knowledge base (KKB), is described. It covers all human kinase domain structures that have been deposited in the Protein Data Bank. All structures are renumbered using a common scheme, which enables efficient crosscomparisons and multiple queries of interest to the kinase field. The common numbering scheme is also used to automatically annotate conserved residues and motifs, and conformationally classify the structures based on the DFG-loop and Helix C. Analyses of residue conservation in the ATP binding site using the full human-kinome-sequence alignment lead to the identification of a conserved hydrogen bond between the hinge region backbone and a glycine in the specificity surface. Furthermore, 90% of kinases are found to have at least one stabilizing interaction for the hinge region, which has not been described before.

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Section: Discussionmentioning

confidence: 99%

An enriched structural kinase database to enable kinome‐wide structure‐based analyses and drug discovery

et al. 2010

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“…The extra-precision (XP) mode of GLIDE was used to achieve an accurate pose prediction. The GLIDE XP mode utilizes an improved scoring function, including a water desolvation energy term and protein-ligand structural motifs that result in enhanced binding affinity [18] . For docking, the receptor structures were preprocessed using protein refinement 1131 www.chinaphar.com Lee BH et al Acta Pharmacologica Sinica npg components in the GLIDE docking package.…”

Section: Pulse Protocols and Analysismentioning

confidence: 99%

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

Lee

Chu

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects. Methods: hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. Results: Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD 90 ) in both concentration-and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC 50 for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold. Conclusion:The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.

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“…The pharmacophore models were generated from the ligand co-crystallized complex structures of these targets using the LigandScout program [12] , and each PBVS was performed using the program Catalyst [13,14] . To avoid the target dependency of docking programs, three docking programs, namely DOCK [15,16] , GOLD [17][18][19][20] , and Glide [21,22] , were used in the DBVS. The results for eight tested targets indicated that the pharmacophore-based method generally outperforms all three docking methods in retrieving actives from databases.…”

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confidence: 99%

Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets

Chen

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim: This study was conducted to compare the efficiencies of two virtual screening approaches, pharmacophore-based virtual screening (PBVS) and docking-based virtual screening (DBVS) methods. Methods: All virtual screens were performed on two data sets of small molecules with both actives and decoys against eight structurally diverse protein targets, namely angiotensin converting enzyme (ACE), acetylcholinesterase (AChE), androgen receptor (AR), D-alanyl-D-alanine carboxypeptidase (DacA), dihydrofolate reductase (DHFR), estrogen receptors α (ERα), HIV-1 protease (HIV-pr), and thymidine kinase (TK). Each pharmacophore model was constructed based on several X-ray structures of protein-ligand complexes. Virtual screens were performed using four screening standards, the program Catalyst for PBVS and three docking programs (DOCK, GOLD and Glide) for DBVS. Results: Of the sixteen sets of virtual screens (one target versus two testing databases), the enrichment factors of fourteen cases using the PBVS method were higher than those using DBVS methods. The average hit rates over the eight targets at 2% and 5% of the highest ranks of the entire databases for PBVS are much higher than those for DBVS. Conclusion: The PBVS method outperformed DBVS methods in retrieving actives from the databases in our tested targets, and is a powerful method in drug discovery. discovery, especially in the cases when no three-dimensional (3D) structural information on the protein target of interest is available. Even when the 3D structures of targets are known, PBVS is also used as a complementary approach to DBVS for pre-processing databases (libraries) of small molecules to remove compounds not possessing features known to be essential for binding or for post-filtering compounds selected by docking approaches [5] . A recent case study by Muthas et al indicated that post-filtering with pharmacophores was shown to increase enrichment rates in their investigated targets compared with docking alone [6] . Several studies have been performed to assess various DBVS methods and compare which docking programs are the most successful in identifying active hits [7][8][9][10] . The conclusion is that no docking program may outperform other docking programs for all the tested targets, and the performance of each tested docking program is highly dependent on the nature of the target binding site [5] .Nevertheless, few case studies for a direct comparison on the performances between PBVS and DBVS have been reported [11] . To gain a general view for the discrimination between these two types of approach in prioritizing actives from a database with decoys, we performed a benchmark comparison between the performances of PBVS and DBVS. Eight structurally diverse protein targets were selected in this study. The pharmacophore models were generated from the ligand co-crystallized complex structures of these targets using the LigandScout program [12] , and each PBVS was performed using the program Catalyst [13,14] . To avoid the target dependency of docking pro...

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Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand Complexes

Cited by 5,619 publications

References 40 publications

An enriched structural kinase database to enable kinome‐wide structure‐based analyses and drug discovery

An enriched structural kinase database to enable kinome‐wide structure‐based analyses and drug discovery

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets

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