The use of multiple target conformers has been applied successfully in virtual screening campaigns; however, a study on how to best combine scores for multiple targets in a hierarchic method that combines rigid and flexible docking is not available. In this study, we used a data set of 59 479 compounds to screen multiple conformers of four distinct protein targets to obtain an adapted and optimized combination of an established hierarchic method that employs the programs FRED and Surflex. Our study was extended and verified by application of our protocol to ten different data sets from the directory of useful decoys (DUD). We quantitated overall method performance in ensemble docking and compared several consensus scoring methods to improve the enrichment during virtual ligand screening. We conclude that one of the methods used, which employs a consensus weighted scoring of multiple target conformers, performs consistently better than methods that do not include such consensus scoring. For optimal overall performance in ensemble docking, it is advisable to first calculate a consensus of FRED results and use this consensus as a sub-data set for Surflex screening. Furthermore, we identified an optimal method for each of the chosen targets and propose how to optimize the enrichment for any target.
In this paper we introduce an new Jacobi-Davidson type eigenvalue solver for a set of commuting matrices, called JD-COMM, used for the global optimization of so-called Minkowski-norm dominated polynomials in several variables. The Stetter-Möller matrix method yields such a set of real non-symmetric commuting matrices since it reformulates the optimization problem as an eigenvalue problem. A drawback of this approach is that the matrix most relevant for computing the global optimum of the polynomial under investigation is usually large and only moderately sparse. However, the other matrices are generally much sparser and have the same eigenvectors because of the commutativity. This fact is used to design the JDCOMM method for this problem: the most relevant matrix is used only in the outer loop and the sparser matrices are exploited in the solution of the correction equation in the inner loop to greatly improve the efficiency of the method. Some numerical examples demonstrate that the method proposed in this paper is more efficient than approaches that work on the main matrix (standard Jacobi-Davidson and implicitly restarted Arnoldi), as well as conventional solvers for computing the global optimum, i.e., SOSTOOLS, GloptiPoly, and PHCpack.
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