Supplementary data are available at Bioinformatics online.
Predicting binding between macromolecule and small molecule is a crucial phase in the field of rational drug design. AutoDock Vina, one of the most widely used docking software released in 2009, uses an empirical scoring function to evaluate the binding affinity between the molecules and employs the iterated local search global optimizer for global optimization, achieving a significantly improved speed and better accuracy of the binding mode prediction compared its predecessor, AutoDock 4. In this paper, we propose further improvement in the local search algorithm of Vina by heuristically preventing some intermediate points from undergoing local search. Our improved version of Vina-dubbed QVina-achieved a maximum acceleration of about 25 times with the average speed-up of 8.34 times compared to the original Vina when tested on a set of 231 protein-ligand complexes while maintaining the optimal scores mostly identical. Using our heuristics, larger number of different ligands can be quickly screened against a given receptor within the same time frame.
Protein-ligand docking is a computational method to identify the binding mode of a ligand and a target protein, and predict the corresponding binding affinity using a scoring function. This method has great value in drug design. After decades of development, scoring functions nowadays typically can identify the true binding mode, but the prediction of binding affinity still remains a major problem. Here we present CScore, a data-driven scoring function using a modified Cerebellar Model Articulation Controller (CMAC) learning architecture, for accurate binding affinity prediction. The performance of CScore in terms of correlation between predicted and experimental binding affinities is benchmarked under different validation approaches. CScore achieves a prediction with R = 0.7668 and RMSE = 1.4540 when tested on an independent dataset. To the best of our knowledge, this result outperforms other scoring functions tested on the same dataset. The performance of CScore varies on different clusters under the leave-clusterout validation approach, but still achieves competitive result. Lastly, the target-specified CScore achieves an even better result with R = 0.8237 and RMSE = 1.0872, trained on a much smaller but more relevant dataset for each target. The large dataset of proteinligand complexes structural information and advances of machine learning techniques enable the data-driven approach in binding affinity prediction. CScore is capable of accurate binding affinity prediction. It is also shown that CScore will perform better if sufficient and relevant data is presented. As there is growth of publicly available structural data, further improvement of this scoring scheme can be expected.
An important issue in designing memetic algorithms (MAs) is the choice of solutions in the population for local refinements, which becomes particularly crucial when solving computationally expensive problems. With single evaluation of the objective/constraint functions necessitating tremendous computational power and time, it is highly desirable to be able to focus search efforts on the regions where the global optimum is potentially located so as not to waste too many function evaluations. For constrained optimization, the global optimum must either be located at the trough of some feasible basin or some particular point along the feasibility boundary. Presented in this paper is an instance of optinformatics [1] where new concept of modeling the feasibility structure of inequalityconstrained optimization problems-dubbed the Feasibility Structure Modeling (FSM)is proposed to perform geometrical predictions of the locations of candidate solutions in the solution space: deep inside any infeasible region, nearby any feasibility boundary, or deep inside any feasible region. This knowledge may be unknown prior to executing MA but it can be mined as the search for the global optimum progresses. As more solutions are generated and subsequently stored in the database, the feasibility structure can thus be approximated more accurately. As an integral part, a new paradigm of incorporating the classification-rather than the regression-into the framework of MAs is introduced, allowing the MAs to estimate the feasibility boundary such that effective assessments of whether or not the candidate solutions should experience local refinements can be made. This eventually helps preventing the unnecessary refinements and consequently reducing the number of function evaluations required to reach the global optimum.
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