Optimization of Cavity-Based Negative Images to Boost Docking Enrichment in Virtual Screening

Molecular docking is a key in silico method used routinely in modern drug discovery projects. Although docking provides high-quality ligand binding predictions, it regularly fails to separate the active compounds from the inactive ones. In negative image-based rescoring (R-NiB), the shape/electrostatic potential (ESP) of docking poses is compared to the negative image of the protein’s ligand binding cavity. While R-NiB often improves the docking yield considerably, the cavity-based models do not reach their full potential without expert editing. Accordingly, a greedy search-driven methodology, brute force negative image-based optimization (BR-NiB), is presented for optimizing the models via iterative editing and benchmarking. Thorough and unbiased training, testing and stringent validation with a multitude of drug targets, and alternative docking software show that BR-NiB ensures excellent docking efficacy. BR-NiB can be considered as a new type of shape-focused pharmacophore modeling, where the optimized models contain only the most vital cavity information needed for effectively filtering docked actives from the inactive or decoy compounds. Finally, the BR-NiB code for performing the automated optimization is provided free-of-charge under MIT license via GitHub (https://github.com/jvlehtonen/brutenib) for boosting the success rates of docking-based virtual screening campaigns. </p

Ligand-Enhanced Negative Images Optimized for Docking Rescoring

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses against the target protein's inverted cavity volume. By optimizing these negative image-based (NIB) models using a greedy search, the docking rescoring yield can be improved massively and consistently. Here, a fundamental modification is implemented to this shape-focused pharmacophore modelling approach-actual ligand 3D coordinates are incorporated into the NIB models for the optimization. This hybrid approach, labelled as ligand-enhanced brute-force negative image-based optimization (LBR-NiB), takes the best from both worlds, i.e., the all-roundedness of the NIB models and the difficult to emulate atomic arrangements of actual protein-bound small-molecule ligands. Thorough benchmarking, focused on proinflammatory targets, shows that the LBR-NiB routinely improves the docking enrichment over prior iterations of the R-NiB methodology. This boost can be massive, if the added ligand information provides truly essential binding information that was lacking or completely missing from the cavity-based NIB model. On a practical level, the results indicate that the LBR-NiB typically works well when the added ligand 3D data originates from a high-quality source, such as X-ray crystallography, and, yet, the NIB model compositions can also sometimes be improved by fusing into them, for example, with flexibly docked solvent molecules. In short, the study demonstrates that the protein-bound ligands can be used to improve the shape/ESP features of the negative images for effective docking rescoring use in virtual screening

GHG balance in drained organic forest soils – data revisited

The study is part of the SNS-120 project ‘Anthropogenic greenhouse gas emissions from organic forest soils: improved inventories and implications for sustainable management’ funded by Nordic Forest Research. http://dev.nordicforestresearch.org/sns-120/201

Probabilistic prediction of contacts in protein-ligand complexes.

We introduce a statistical method for evaluating atomic level 3D interaction patterns of protein-ligand contacts. Such patterns can be used for fast separation of likely ligand and ligand binding site combinations out of all those that are geometrically possible. The practical purpose of this probabilistic method is for molecular docking and scoring, as an essential part of a scoring function. Probabilities of interaction patterns are calculated conditional on structural x-ray data and predefined chemical classification of molecular fragment types. Spatial coordinates of atoms are modeled using a Bayesian statistical framework with parametric 3D probability densities. The parameters are given distributions a priori, which provides the possibility to update the densities of model parameters with new structural data and use the parameter estimates to create a contact hierarchy. The contact preferences can be defined for any spatial area around a specified type of fragment. We compared calculated contact point hierarchies with the number of contact atoms found near the contact point in a reference set of x-ray data, and found that these were in general in a close agreement. Additionally, using substrate binding site in cathechol-O-methyltransferase and 27 small potential binder molecules, it was demonstrated that these probabilities together with auxiliary parameters separate well ligands from decoys (true positive rate 0.75, false positive rate 0). A particularly useful feature of the proposed Bayesian framework is that it also characterizes predictive uncertainty in terms of probabilities, which have an intuitive interpretation from the applied perspective

Ligand-Enhanced Negative Images Optimized for Docking Rescoring

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses against the target protein&rsquo;s inverted cavity volume. By optimizing these negative image-based (NIB) models using a greedy search, the docking rescoring yield can be improved massively and consistently. Here, a fundamental modification is implemented to this shape-focused pharmacophore modelling approach&mdash;actual ligand 3D coordinates are incorporated into the NIB models for the optimization. This hybrid approach, labelled as ligand-enhanced brute-force negative image-based optimization (LBR-NiB), takes the best from both worlds, i.e., the all-roundedness of the NIB models and the difficult to emulate atomic arrangements of actual protein-bound small-molecule ligands. Thorough benchmarking, focused on proinflammatory targets, shows that the LBR-NiB routinely improves the docking enrichment over prior iterations of the R-NiB methodology. This boost can be massive, if the added ligand information provides truly essential binding information that was lacking or completely missing from the cavity-based NIB model. On a practical level, the results indicate that the LBR-NiB typically works well when the added ligand 3D data originates from a high-quality source, such as X-ray crystallography, and, yet, the NIB model compositions can also sometimes be improved by fusing into them, for example, with flexibly docked solvent molecules. In short, the study demonstrates that the protein-bound ligands can be used to improve the shape/ESP features of the negative images for effective docking rescoring use in virtual screening

A ROC curve illustrating the functionality of the probabilistic model.

<p>The 12 threshold probabilities separating ligands from decoys that were used for calculating the characteristics are 0.05, 0.1, …, 0.3, 0.4, 0.5, 0.65, 0.75, 0.8 and 0.9.</p

The volumes used for calculations in Examples 1,3 and 4.

<p>Here would be located in the center of the volume, both radially and with respect to the solid angle. The center of the volume of Example 2 (not shown explicitly) is located on the axis defined by the vector connecting Atom1 to Main-atom, i.e. on the positive x-axis in this figure.</p

Classification of contact atoms, or targets.

<p>The target classification was adopted from the previous work of Rantanen et al. (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049216#s1" target="_blank">Introduction</a>) while some classes were excluded. As in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049216#pone-0049216-t002" target="_blank">Table 2</a>, the classes are not renumbered for the consistency of notation.</p

Contacts for nitrogen, singly bonded to a planar structure (f29) — e.g. in carbamoyl group.

<p>showing distance dependence for target class <b>C14</b> (carbonyl oxygen). The scatter plot contains all <b>C14</b> target atoms in the training data and the densities show which directions are emphasized at distances 2.7, 2.98 and 3.26 Å.</p

Contacts in the active site of PNMT (a methyltransferase) for R-noradrenaline tail hydroxyl group.

<p>Three amino acid residues (ASP B267, GLU B219 and TYR B222) were considered as contacts.</p