A new test set for validating predictions of protein–ligand interaction

Nissink, J. Willem M.; Murray, Christopher W.; Hartshorn, Mike; Verdonk, Marcel L.; Cole, Jason C.; Taylor, Robin

doi:10.1002/prot.10232

Cited by 425 publications

(440 citation statements)

References 23 publications

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“…[53] 2.3 Molecular docking Selection of dienophiles and generation of initial studies were accomplished by docking simulations, using the GOLD Suite. [54,55,56,57] The docking procedure was conducted according to the following protocol: The built-in genetic algorithm (GA) was used to generate different poses, which were evaluated with the ChemScore scoring function. [58,59] The space of possible poses was limited to relevant ones by inducing hydrogen bond constraints between the dienophile carbonyl oxygen and T40-NH, T40-O γ H and Q106-NH.…”

Section: Enzyme Variantsmentioning

confidence: 99%

Computational design of a lipase for catalysis of the Diels-Alder reaction

et al. 2010

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Combined molecular docking, molecular dynamics (MD) and density functional theory (DFT) studies have been employed to study catalysis of the Diels-Alder reaction by a modified lipase. Six variants of the versatile enzyme {\em Candida Antarctica} lipase B (CALB) have been rationally engineered {\em in silico} based on the specific characteristics of the pericyclic addition. A kinetic analysis reveals that hydrogen bond stabilization of the transition state and substrate binding are key components of the catalytic process. In the case of substrate binding, which has the greater potential for optimization, both binding strength and positioning of the substrates are important for catalytic efficiency. The binding strength is determined by hydrophobic interactions and can be tuned by careful selection of solvent and substrates. The MD simulations show that substrate positioning is sensitive to cavity shape and size, and can be controlled by a few rational mutations. The well-documented S105A mutation is essential to enable sufficient space in the vicinity of the oxyanion hole. Moreover, bulky residues on the edge of the active site hinders the formation of a sandwich-like near-attack conformer (NAC), and the I189A mutation is needed to obtain enough space above the face of the $\alpha$,$\beta$-double bond on the dienophile. The double mutant S105A/I189A performs quite well for two of three dienophiles. Based on binding constants and NAC energies obtained from MD simulations combined with activation energies from DFT computations, relative catalytic rates ($v_{cat}/v_{uncat}$) of up to $10^3$ are predicted.Response to Reviewers: We are happy with the favorable comments by the reviewers. We have have corrected the manuscript as suggested by reviewer 1 1. A sentence explaining catalytic promiscuity has been added. 2. A paragraph discussing the relationship between the NAC concept and the Reaction Force has been added.We have shortened the manuscript as suggested by reviewer 2. In particular, we have moved information regarding the structural relaxation of protein structure in MD simulations to the supplementary material. Abstract Combined molecular docking, molecular dynamics (MD) and density functional theory (DFT) studies have been employed to study catalysis of the DielsAlder reaction by a modified lipase. Six variants of the versatile enzyme Candida Antarctica lipase B (CALB) have been rationally engineered in silico based on the specific characteristics of the pericyclic addition. A kinetic analysis reveals that hydrogen bond stabilization of the transition state and substrate binding are key components of the catalytic process. In the case of substrate binding, which has the greater potential for optimization, both binding strength and positioning of the substrates are important for catalytic efficiency. The binding strength is determined by hydrophobic interactions and can be tuned by careful selection of solvent and substrates. The MD simulations show that substrate positioning is sensitive to cavity s...

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Section: Enzyme Variantsmentioning

confidence: 99%

Computational design of a lipase for catalysis of the Diels-Alder reaction

et al. 2010

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“…For the docking-based virtual screening, three docking programs, DOCK (UCSF) [15,16] , GOLD (Cambridge Crystallographic Data Center) [17][18][19][20] and Glide (Schrödinger, Inc) [21,22] , were used in this study for the purpose of getting unbiased results of docking. The detailed procedures for the virtual screenings using these three docking programs are described in the Supplementary Information.…”

Section: Virtual Screeningmentioning

confidence: 99%

“…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.…”

mentioning

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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“…The utility of iGEMDOCK is well established (78% success rates) from its testing on 305 proteinligand Astex set [24]. Furthermore, the post-screening analysis and clustering of docked poses based on the high energy scores and pharmacological interactions makes iGEMDOCK more relevant for the present studies (table 1) shows the docking result of trimethoprim, paclitaxel and vinblastine with three subunits (AcrA, AcrB and TolC) of S. Typhi.…”

Section: Resultsmentioning

confidence: 98%

Anticancer Drugs as Prospective Efflux Pump Inhibitors for Salmonella Typhi Produce Conflicting Results in in Silico and in Vitro Studies

Gupta

Gautam

Rai

2016

Int J Pharm Pharm Sci

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Objective: Anticancer drugs paclitaxel and vinblastine were tested for their potential as efflux pump inhibitors for Salmonella Typhi-based on in silico and in vitro studies.Methods: Three-dimensional protein models of AcrAB-TolC of Salmonella Typhi were generated by online server PHYRE-2. The quality of 3D structures was assessed by PROCHECK, SWISS MODEL. Docking analysis of anticancer drugs with AcrA, AcrB and TolC subunits were performed after refining the homology models with Modrefiner. Salmonella Typhi (S. Typhi) efflux pump activity was measured by ethidium bromide (EtBr) cartwheel and semi-automated fluorometry methods respectively. Fluorescence intensity in bacterial colonies was measured under different treatment conditions (with or without drugs) on Muller Hinton agar (MHA) plates containing EtBr in cartwheel assay. EtBr efflux assay was determined following the loading of bacteria with EtBr and fluorescence was recorded over fixed time period with the help of fluorescent spectrophotometer. The results obtained were compared with the control.Results: Efflux pump inhibitor (EPIs) activity of paclitaxel and vinblastine determined by EtBr cartwheel assay registered no activity whereas semiautomated fluorescent assay revealed marginal activity when compared to control. Conclusion:We report the conflicting result of in silico and in vitro studies in predicting the antimicrobial effect of mainstream anticancer drugs as efflux pump inhibitors for Salmonella Typhi.

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A new test set for validating predictions of protein–ligand interaction

Cited by 425 publications

References 23 publications

Computational design of a lipase for catalysis of the Diels-Alder reaction

Computational design of a lipase for catalysis of the Diels-Alder reaction

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

Anticancer Drugs as Prospective Efflux Pump Inhibitors for Salmonella Typhi Produce Conflicting Results in in Silico and in Vitro Studies

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