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Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise.

ABSTRACT: We describe a general methodology for designing an empirical scoring function and provide smina, a version of AutoDock Vina specially optimized to support high-throughput scoring and user-specified custom scoring functions. Using our general method, the unique capabilities of smina, a set of default interaction terms from AutoDock Vina, and the CSAR (Community Structure-Activity Resource) 2010 data set, we created a custom scoring function and evaluated it in the context of the CSAR 2011 benchmarking exercise. We find that our custom scoring function does a better job sampling low RMSD poses when crossdocking compared to the default AutoDock Vina scoring function. The design and application of our method and scoring function reveal several insights into possible improvements and the remaining challenges when scoring and ranking putative ligands.

SUBMITTER: Koes DR

PROVIDER: S-EPMC3726561 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise.

Koes David Ryan DR Baumgartner Matthew P MP Camacho Carlos J CJ

Journal of chemical information and modeling 20130212 8

We describe a general methodology for designing an empirical scoring function and provide smina, a version of AutoDock Vina specially optimized to support high-throughput scoring and user-specified custom scoring functions. Using our general method, the unique capabilities of smina, a set of default interaction terms from AutoDock Vina, and the CSAR (Community Structure-Activity Resource) 2010 data set, we created a custom scoring function and evaluated it in the context of the CSAR 2011 benchma ...[more]

PMID: 23379370

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Project description:The Community Structure-Activity Resource (CSAR) recently held its first blinded exercise based on data provided by Abbott, Vertex, and colleagues at the University of Michigan, Ann Arbor. A total of 20 research groups submitted results for the benchmark exercise where the goal was to compare different improvements for pose prediction, enrichment, and relative ranking of congeneric series of compounds. The exercise was built around blinded high-quality experimental data from four protein targets: LpxC, Urokinase, Chk1, and Erk2. Pose prediction proved to be the most straightforward task, and most methods were able to successfully reproduce binding poses when the crystal structure employed was co-crystallized with a ligand from the same chemical series. Multiple evaluation metrics were examined, and we found that RMSD and native contact metrics together provide a robust evaluation of the predicted poses. It was notable that most scoring functions underpredicted contacts between the hetero atoms (i.e., N, O, S, etc.) of the protein and ligand. Relative ranking was found to be the most difficult area for the methods, but many of the scoring functions were able to properly identify Urokinase actives from the inactives in the series. Lastly, we found that minimizing the protein and correcting histidine tautomeric states positively trended with low RMSD for pose prediction but minimizing the ligand negatively trended. Pregenerated ligand conformations performed better than those that were generated on the fly. Optimizing docking parameters and pretraining with the native ligand had a positive effect on the docking performance as did using restraints, substructure fitting, and shape fitting. Lastly, for both sampling and ranking scoring functions, the use of the empirical scoring function appeared to trend positively with the RMSD. Here, by combining the results of many methods, we hope to provide a statistically relevant evaluation and elucidate specific shortcomings of docking methodology for the community.

Project description:BackgroundThe Ankylosing Spondylitis Association of Switzerland (SVMB) aimed to implement physical activity recommendations (PAR) within their exercise groups (EGs). The PAR promote exercise in all fitness dimensions at the correct dose. To implement the PAR within EGs, they were translated into a new EG concept with five key activities: (a) training for supervising physiotherapists (PTs), (b) correctly dosed exercises in all fitness dimensions, (c) exercise counselling, (d) bi-annual fitness assessments, and (e) individual exercise training, in addition to EG. All these activities were realized in close coordination with SVMB management.ObjectivesTo analyse the implementation success by evaluating adherence/fidelity, feasibility, and satisfaction at the patient, PTs, and organisational level.MethodsThe five key activities of the new EG concept were developed, executed, and assessed after 6 months. The primary outcomes for implementation success were adherence of patients to the recommended exercise behaviour, self-reported by electronic diary; fidelity of PTs to the new concept, self-reported by diary; SVMB organisational changes. Secondary outcomes were feasibility and satisfaction with the new EG concept at all three levels. The tertiary outcome, to evaluate the effectiveness of PAR, was patient fitness, assessed through fitness assessments.Results30 patients with axSpA (ten women, mean age 58 ± 9 years) and four PTs (three women, mean age 46 ± 9 years) participated. The patients' self-reporting of adherence to the PAR was insufficient (43%), possibly due to technical problems with the electronic dairy. The PTs' fidelity to the new EG concept was satisfactory. On all levels, the new concept was generally perceived as feasible and useful for supporting personalised exercise.The frequency of exercise counselling and the fitness assessments was found by patients and PTs to be too high and rigid. Patients' cardiorespiratory fitness [ES 1.21 (95%CI 0.59, 1.89)] and core strength [ES 0.61 (95%CI 0.18, 1.06)] improved over the 6 months.ConclusionsThe pilot implementation of PAR showed acceptance and satisfaction to be sufficient, thus confirming the need for evidence-based EGs, provided by a patient organisation in order to support active PA behaviour. However, adaptations are necessary to increase its feasibility for nationwide implementation.Trial registrationSNCTP, SNCTP000002880. Registered 31 May 2018, https://www.kofam.ch/en/snctp-portal/search/0/study/42491 .

Dataset Information

Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise.

Publications

Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise.

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