With an increasing interest in RNA therapeutics and for targeting RNA to treat disease, there is a need for the tools used in protein-based drug design, particularly DOCKing algorithms, to be ...extended or adapted for nucleic acids. Here, we have compiled a test set of RNA-ligand complexes to validate the ability of the DOCK suite of programs to successfully recreate experimentally determined binding poses. With the optimized parameters and a minimal scoring function, 70% of the test set with less than seven rotatable ligand bonds and 26% of the test set with less than 13 rotatable bonds can be successfully recreated within 2 A heavy-atom RMSD. When DOCKed conformations are rescored with the implicit solvent models AMBER generalized Born with solvent-accessible surface area (GB/SA) and Poisson-Boltzmann with solvent-accessible surface area (PB/SA) in combination with explicit water molecules and sodium counterions, the success rate increases to 80% with PB/SA for less than seven rotatable bonds and 58% with AMBER GB/SA and 47% with PB/SA for less than 13 rotatable bonds. These results indicate that DOCK can indeed be useful for structure-based drug design aimed at RNA. Our studies also suggest that RNA-directed ligands often differ from typical protein-ligand complexes in their electrostatic properties, but these differences can be accommodated through the choice of potential function. In addition, in the course of the study, we explore a variety of newly added DOCK functions, demonstrating the ease with which new functions can be added to address new scientific questions.
In this paper we describe the search strategies developed for docking flexible molecules to macomolecular sites that are incorporated into the widely distributed DOCK software, version 4.0. The ...search strategies include incremental construction and random conformation search and utilize the existing Coulombic and Lennard-Jones grid-based scoring function. The incremental construction strategy is tested with a panel of 15 crystallographic testcases, created from 12 unique complexes whose ligands vary in size and flexibility. For all testcases, at least one docked position is generated within 2 A of the crystallographic position. For 7 of 15 testcases, the top scoring position is also within 2 A of the crystallographic position. The algorithm is fast enough to successfully dock a few testcases within seconds and most within 100 s. The incremental construction and the random search strategy are evaluated as database docking techniques with a database of 51 molecules docked to two of the crystallographic testcases. Incremental construction outperforms random search and is fast enough to reliably rank the database of compounds within 15 s per molecule on an SGI R10000 cpu.
Apolipoprotein (apo) E4 is a major risk factor for Alzheimer's disease, and many studies have suggested that apoE has isoformspecific effects on the deposition or clearance of amyloid β (Aβ) ...peptides. We examined the effects of apoE isoforms on the processing of amyloid precursor protein (APP) and on Aβ production in rat neuroblastoma B103 cells stably transfected with human wild-type APP695 (B103-APP). Lipid-poor apoE4 increased Aβ production in B103-APP cells to a greater extent than lipid-poor apoE3 (60% vs. 30%) due to more pronounced stimulation of APP recycling by apoE4 than apoE3. The difference in Aβ production was abolished by preincubating the cells with the receptor-associated protein (25 nM), which blocks the low-density lipoprotein receptor-related protein (LRP) pathway, or by reducing LRP expression by small interference RNA. The differences were also attenuated by replacing Arg-61 with threonine in apoE4 or pretreating apoE4 with small molecules, both of which abolish apoE4 intramolecular domain interaction. Thus, apoE4 appears to modulate APP processing and Aβ production through both the LRP pathway and domain interaction. These findings provide insights into why apoE4 is associated with increased risk for Alzheimer's disease and may represent a potential target for drug development.
Absolute free energies of hydration (ΔG hyd) for more than 500 neutral and charged compounds have been computed, using Poisson−Boltzmann (PB) and Generalized Born (GB) continuum methods plus a ...solvent-accessible surface area (SA) term, to evaluate the accuracy of eight simple point-charge models used in molecular modeling. The goal is to develop improved procedures and protocols for protein−ligand binding calculations and virtual screening (docking). The best overall PBSA and GBSA results, in comparison with experimental ΔG hyd values for small molecules, were obtained using MSK, RESP, or ChelpG charges obtained from ab initio calculations using 6-31G* wave functions. Correlations using semiempirical (AM1BCC, AM1CM2, and PM3CM2) or empirical (Gasteiger-Marsili and MMFF94) methods yielded mixed results, particularly for charged compounds. For neutral compounds, the AM1BCC method yielded the best agreement with experimental results. In all cases, the PBSA and GBSA results are highly correlated (overall r 2 = 0.94), which highlights the fact that various partial charge models influence the final results much more than which continuum method is used to compute hydration free energies. Overall improved agreement with experimental results was demonstrated using atom-based constants in place of a single surface area term. Sets of optimized SA constants, suitable for use with a given charge model, were derived by fitting to the difference in experimental free energies and polar continuum results. The use of optimized atom-based SA constants for the computation of ΔG hyd can fine-tune already reasonable agreement with experimental results, ameliorate gross deficiencies in any particular charge model, account for nonoptimal radii, or correct for systematic errors.
We report on the development and validation of a new version of DOCK. The algorithm has been rewritten in a modular format, which allows for easy implementation of new scoring functions, sampling ...methods and analysis tools. We validated the sampling algorithm with a test set of 114 protein-ligand complexes. Using an optimized parameter set, we are able to reproduce the crystal ligand pose to within 2 A of the crystal structure for 79% of the test cases using our rigid ligand docking algorithm with an average run time of 1 min per complex and for 72% of the test cases using our flexible ligand docking algorithm with an average run time of 5 min per complex. Finally, we perform an analysis of the docking failures in the test set and determine that the sampling algorithm is generally sufficient for the binding pose prediction problem for up to 7 rotatable bonds; i.e. 99% of the rigid ligand docking cases and 95% of the flexible ligand docking cases are sampled successfully. We point out that success rates could be improved through more advanced modeling of the receptor prior to docking and through improvement of the force field parameters, particularly for structures containing metal-based cofactors.
Most drugs have been discovered in random screens or by exploiting information about macromolecular receptors. One source of this information is in the structures of critical proteins and nucleic ...acids. The structure-based approach to design couples this information with specialized computer programs to propose novel enzyme inhibitors and other therapeutic agents. Iterated design cycles have produced compounds now in clinical trials. The combination of molecular structure determination and computation is emerging as an important tool for drug development. These ideas will be applied to acquired immunodeficiency syndrome (AIDS) and bacterial drug resistance.
In this work, an efficient strategy was presented to search drug leads for human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) using hierarchical database screenings, which included ...a pharmacophore model, multiple-conformation rigid docking, solvation docking, and molecular mechanics−Poisson−Boltzmann/surface area (MM−PB/SA) sequentially. Encouraging results were achieved in searching a refined available chemical directory (ACD) database: the enrichment factor after the first three filters was estimated to be 25-fold; the hit rate for all the four filters was predicted to be 41% in a control test using 37 known HIV-1 non-nucleoside reverse transcriptase inhibitors; 10 out of 30 promising solvation-docking hits had MM−PB/SA binding free energies better than −6.8 kcal/mol and the best one, HIT15, had −17.0 kcal/mol. In conclusion, the hierarchical multiple-filter database searching strategy is an attractive strategy in drug lead exploration.
Darwinian Docking Kuntz, Irwin D.
Journal of computer-aided molecular design,
2012/1, Volume:
26, Issue:
1
Journal Article
Peer reviewed
The Darwinian model of evolution is an optimization strategy that can be adapted to docking. It differs from the common use of genetic algorithms, primarily in its acceptance of diverse solutions ...over finding "global" optima. A related problem is selecting compounds using multiple criteria. I discuss these ideas and present the outlines of a protocol for selecting "hits" and "leads" in drug discovery.
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