A comparison between 2D and 3D descriptors in QSAR modeling based on bio-active conformations.

QSAR models are widely and successfully used in many research areas. The success of such models highly depends on molecular descriptors typically classified as 1D, 2D, 3D, or 4D. While 3D information is likely important, e. g., for modeling ligand-protein binding, previous comparisons between the performances of 2D and 3D descriptors were inconclusive. Yet in such comparisons the modeled ligands were not necessarily represented by their bioactive conformations. With this in mind, we mined the PDB for sets of protein-ligand complexes sharing the same protein for which uniform activity data were reported. The results, totaling 461 structures spread across six series were compiled into a carefully curated, first of its kind dataset in which each ligand is represented by its bioactive conformation. Next, each set was characterized by 2D, 3D and 2D + 3D descriptors and modeled using three machine learning algorithms, namely, k-Nearest Neighbors, Random Forest and Lasso Regression. Models' performances were evaluated on external test sets derived from the parent datasets either randomly or in a rational manner. We found that many more significant models were obtained when combining 2D and 3D descriptors. We attribute these improvements to the ability of 2D and 3D descriptors to code for different, yet complementary molecular properties.

Towards an Enrichment Optimization Algorithm (EOA)-based Target Specific Docking Functions for Virtual Screening.

Docking-based virtual screening (VS) is a common starting point in many drug discovery projects. While ligand-based approaches may sometimes provide better results, the advantage of docking lies in its ability to provide reliable ligand binding modes and approximated binding free energies, two factors that are important for hit selection and optimization. Most docking programs were developed to be as general as possible and consequently their performances on specific targets may be sub-optimal. With this in mind, in this work we present a method for the development of target-specific scoring functions using our recently reported Enrichment Optimization Algorithm (EOA). EOA derives QSAR models in the form of multiple linear regression (MLR) equations by optimizing an enrichment-like metric. Since EOA requires target-specific active and inactive (or decoy) compounds, we retrieved such data for six targets from the DUD-E database, and used them to re-derive the weights associated with the components that make up GOLD's ChemPLP scoring function yielding target-specific, modified functions. We then used the original ChemPLP function in small-scale VS experiments on the six targets and subsequently rescored the resulting poses with the modified functions. In addition, we used the modified functions for compounds re-docking. We found that in many although not all cases, either rescoring the original ChemPLP poses or repeating the entire docking process with the modified functions, yielded better results in terms of AUC and EF1% , two metrics, common for the evaluation of VS performances. While work on additional datasets and docking tools is clearly required, we propose that the results obtained thus far hint to the potential benefits in using EOA-based optimization for the derivation of target-specific functions in the context of virtual screening. To this end, we discuss the downsides of the methods and how it could be improved.

PARP1: Structural insights and pharmacological targets for inhibition.

Poly(ADP-ribose) polymerase 1 (PARP1, also known as ADPRT1) is a multifunctional human ADP-ribosyltransferase. It plays a role in multiple DNA repair pathways, including the base excision repair (BER), non-homologous end joining (NHEJ), homologous recombination (HR), and Okazaki-fragment processing pathways. In response to DNA strand breaks, PARP1 covalently attaches ADP-ribose moieties to arginine, glutamate, aspartate, cysteine, lysine, and serine acceptor sites on both itself and other proteins. This signal recruits DNA repair proteins to the site of DNA damage. PARP1 binding to these sites enhances ADP-ribosylation via allosteric communication between the distant DNA binding and catalytic domains. In this review, we provide a general overview of PARP1 and emphasize novel potential approaches for pharmacological inhibition. Clinical PARP1 inhibitors bind the catalytic pocket, where they directly interfere with ADP-ribosylation. Some inhibitors may further enhance potency by "trapping" PARP1 on DNA via an allosteric mechanism, though this proposed mode of action remains controversial. PARP1 inhibitors are used clinically to treat some cancers, but resistance is common, so novel pharmacological approaches are urgently needed. One approach may be to design novel small molecules that bind at inter-domain interfaces that are essential for PARP1 allostery. To illustrate these points, this review also includes instructive videos showing PARP1 structures and mechanisms.

A Comparison between Enrichment Optimization Algorithm (EOA)-Based and Docking-Based Virtual Screening.

Virtual screening (VS) is a well-established method in the initial stages of many drug and material design projects. VS is typically performed using structure-based approaches such as molecular docking, or various ligand-based approaches. Most docking tools were designed to be as global as possible, and consequently only require knowledge on the 3D structure of the biotarget. In contrast, many ligand-based approaches (e.g., 3D-QSAR and pharmacophore) require prior development of project-specific predictive models. Depending on the type of model (e.g., classification or regression), predictive ability is typically evaluated using metrics of performance on either the training set (e.g.,QCV2) or the test set (e.g., specificity, selectivity or QF1/F2/F32). However, none of these metrics were developed with VS in mind, and consequently, their ability to reliably assess the performances of a model in the context of VS is at best limited. With this in mind we have recently reported the development of the enrichment optimization algorithm (EOA). EOA derives QSAR models in the form of multiple linear regression (MLR) equations for VS by optimizing an enrichment-based metric in the space of the descriptors. Here we present an improved version of the algorithm which better handles active compounds and which also takes into account information on inactive (either known inactive or decoy) compounds. We compared the improved EOA in small-scale VS experiments with three common docking tools, namely, Glide-SP, GOLD and AutoDock Vina, employing five molecular targets (acetylcholinesterase, human immunodeficiency virus type 1 protease, MAP kinase p38 alpha, urokinase-type plasminogen activator, and trypsin I). We found that EOA consistently outperformed all docking tools in terms of the area under the ROC curve (AUC) and EF1% metrics that measured the overall and initial success of the VS process, respectively. This was the case when the docking metrics were calculated based on a consensus approach and when they were calculated based on two different sets of single crystal structures. Finally, we propose that EOA could be combined with molecular docking to derive target-specific scoring functions.

Evaluation of QSAR Equations for Virtual Screening.

Quantitative Structure Activity Relationship (QSAR) models can inform on the correlation between activities and structure-based molecular descriptors. This information is important for the understanding of the factors that govern molecular properties and for designing new compounds with favorable properties. Due to the large number of calculate-able descriptors and consequently, the much larger number of descriptors combinations, the derivation of QSAR models could be treated as an optimization problem. For continuous responses, metrics which are typically being optimized in this process are related to model performances on the training set, for example, R2 and QCV2. Similar metrics, calculated on an external set of data (e.g., QF1/F2/F32), are used to evaluate the performances of the final models. A common theme of these metrics is that they are context -" ignorant". In this work we propose that QSAR models should be evaluated based on their intended usage. More specifically, we argue that QSAR models developed for Virtual Screening (VS) should be derived and evaluated using a virtual screening-aware metric, e.g., an enrichment-based metric. To demonstrate this point, we have developed 21 Multiple Linear Regression (MLR) models for seven targets (three models per target), evaluated them first on validation sets and subsequently tested their performances on two additional test sets constructed to mimic small-scale virtual screening campaigns. As expected, we found no correlation between model performances evaluated by "classical" metrics, e.g., R2 and QF1/F2/F32 and the number of active compounds picked by the models from within a pool of random compounds. In particular, in some cases models with favorable R2 and/or QF1/F2/F32 values were unable to pick a single active compound from within the pool whereas in other cases, models with poor R2 and/or QF1/F2/F32 values performed well in the context of virtual screening. We also found no significant correlation between the number of active compounds correctly identified by the models in the training, validation and test sets. Next, we have developed a new algorithm for the derivation of MLR models by optimizing an enrichment-based metric and tested its performances on the same datasets. We found that the best models derived in this manner showed, in most cases, much more consistent results across the training, validation and test sets and outperformed the corresponding MLR models in most virtual screening tests. Finally, we demonstrated that when tested as binary classifiers, models derived for the same targets by the new algorithm outperformed Random Forest (RF) and Support Vector Machine (SVM)-based models across training/validation/test sets, in most cases. We attribute the better performances of the Enrichment Optimizer Algorithm (EOA) models in VS to better handling of inactive random compounds. Optimizing an enrichment-based metric is therefore a promising strategy for the derivation of QSAR models for classification and virtual screening.

AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization.

We here present AutoGrow4, an open-source program for semi-automated computer-aided drug discovery. AutoGrow4 uses a genetic algorithm to evolve predicted ligands on demand and so is not limited to a virtual library of pre-enumerated compounds. It is a useful tool for generating entirely novel drug-like molecules and for optimizing preexisting ligands. By leveraging recent computational and cheminformatics advancements, AutoGrow4 is faster, more stable, and more modular than previous versions. It implements new docking-program compatibility, chemical filters, multithreading options, and selection methods to support a wide range of user needs. To illustrate both de novo design and lead optimization, we here apply AutoGrow4 to the catalytic domain of poly(ADP-ribose) polymerase 1 (PARP-1), a well characterized DNA-damage-recognition protein. AutoGrow4 produces drug-like compounds with better predicted binding affinities than FDA-approved PARP-1 inhibitors (positive controls). The predicted binding modes of the AutoGrow4 compounds mimic those of the known inhibitors, even when AutoGrow4 is seeded with random small molecules. AutoGrow4 is available under the terms of the Apache License, Version 2.0. A copy can be downloaded free of charge from http://durrantlab.com/autogrow4.

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening.

Computational techniques such as structure-based virtual screening require carefully prepared 3D models of potential small-molecule ligands. Though powerful, existing commercial programs for virtual-library preparation have restrictive and/or expensive licenses. Freely available alternatives, though often effective, do not fully account for all possible ionization, tautomeric, and ring-conformational variants. We here present Gypsum-DL, a free, robust open-source program that addresses these challenges. As input, Gypsum-DL accepts virtual compound libraries in SMILES or flat SDF formats. For each molecule in the virtual library, it enumerates appropriate ionization, tautomeric, chiral, cis/trans isomeric, and ring-conformational forms. As output, Gypsum-DL produces an SDF file containing each molecular form, with 3D coordinates assigned. To demonstrate its utility, we processed 1558 molecules taken from the NCI Diversity Set VI and 56,608 molecules taken from a Distributed Drug Discovery (D3) combinatorial virtual library. We also used 4463 high-quality protein-ligand complexes from the PDBBind database to show that Gypsum-DL processing can improve virtual-screening pose prediction. Gypsum-DL is available free of charge under the terms of the Apache License, Version 2.0.