CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

Enhanced Calculation of Property Distributions in Chemical Fragment Spaces.

Chemical fragment spaces exceed traditional virtual compound libraries by orders of magnitude, making them ideal search spaces for drug design projects. However, due to their immense size, they are not compatible with traditional analysis and search algorithms that rely on the enumeration of molecules. In this paper, we present SpaceProp2, an evolution of the SpaceProp algorithm, which enables the calculation of exact property distributions for chemical fragment spaces without enumerating them.

Target 2035 - an update on private sector contributions.

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins.

CACHE (Critical Assessment of Computational Hit-finding Experiments): A public-private partnership benchmarking initiative to enable the development of computational methods for hit-finding.

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios.

Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design.

OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist.

Comparison of Large Chemical Spaces.

Chemical libraries are commonplace in computer-aided drug discovery, and assessing their overlap/complementarity is a routine task. For this purpose, different techniques are applied, ranging from exact matching to comparing physicochemical properties. However, these techniques are applicable only if the compound sets are not too big.

The power of combining phenotypic and target-focused drug discovery.

A fierce dispute has arisen between the supporters of phenotypic and target-focused screening regarding which path grants the higher probability of successful drug development. A chance to reconcile these two approaches lies in successful target deconvolution (TD) after phenotypic screens. But, despite the panoply of available in vitro TD methods, the task of matching a phenotypically active compound with a biomolecular target remains challenging.

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization.

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble.

Identification of new potent GPR119 agonists by combining virtual screening and combinatorial chemistry.

Virtual screening in a huge collection of virtual combinatorial libraries has led to the identification of two new structural classes of GPR119 agonists with submicromolar in vitro potencies. Herein, we describe the virtual screening process involving feature trees fragment space searches followed by a 3D postprocessing step. The in silico findings were then filtered and prioritized, and finally, combinatorial libraries of target molecules were synthesized.

Design of combinatorial libraries for the exploration of virtual hits from fragment space searches with LoFT.

A case study is presented illustrating the design of a focused CDK2 library. The scaffold of the library was detected by a feature trees search in a fragment space based on reactions from combinatorial chemistry. For the design the software LoFT (Library optimizer using Feature Trees) was used.

Improving similarity-driven library design: customized matching and regioselective feature trees.

Reduced graph descriptors, like feature trees, are frequently applied in cases where the relative arrangement of functional groups is more important than exact substructure matches. Due to their ability to deal with fragmented molecules, they are well-suited for fragment space search and library design. We recently presented LoFT, a novel focused library design approach based on feature trees.

LoFT: similarity-driven multiobjective focused library design.

We present LoFT, a tool for focused combinatorial library design. LoFT provides a set of algorithms, constructing a focused library from a chemical fragment space under optimization of multiple design criteria. A weighted multiobjective scoring function based on physicochemical descriptors is employed for traversing the chemical search space.

Searching Fragment Spaces with feature trees.

Virtual combinatorial chemistry easily produces billions of compounds, for which conventional virtual screening cannot be performed even with the fastest methods available. An efficient solution for such a scenario is the generation of Fragment Spaces, which encode huge numbers of virtual compounds by their fragments/reagents and rules of how to combine them. Similarity-based searches can be performed in such spaces without ever fully enumerating all virtual products.

Interactions of Streptomyces griseus aminopeptidase with a methionine product analogue: a structural study at 1.53 A resolution.

SGAP is an aminopeptidase present in the extracellular fluid of Streptomyces griseus cultures. It is a double-zinc enzyme with a strong preference for large hydrophobic amino-terminus residues. It is a monomeric (30 kDa) heat-stable enzyme, with a high and efficient catalytic activity modulated by calcium ions.

Flexsim-X: a method for the detection of molecules with similar biological activity.

We describe the development of the method Flexsim-X, which can be used to detect molecules with similar biological activity. This procedure is based on comparing virtual affinity fingerprints made up from docking scores of the molecules with respect to a reference set of binding sites. Using a test data set consisting of ligands from five different activity classes and randomly chosen compounds, the reference panel of binding sites was optimized in terms of size and composition.

Importance of anchor group positioning in protein loop prediction.

The aim of loop prediction in protein homology modeling is to connect the main chain ends of two successive regions, conserved in template and target structures by protein fragments that are as similar to the target as possible. For the development of a new loop prediction method, examples of insertions and deletions were searched automatically in data sets of structurally aligned protein pairs. Three different criteria were applied for the determination of the positions where the main chain conformations of the proteins begin to differ, i.

Inhibition of Streptomyces griseus aminopeptidase and effects of calcium ions on catalysis and binding--comparisons with the homologous enzyme Aeromonas proteolytica aminopeptidase.

Streptomyces griseus aminopeptidase is a zinc metalloenzyme containing 2 mol zinc/mol protein, similar to the homologous enzyme Aeromonas proteolytica aminopeptidase. In addition, a unique Ca2+-binding site has been identified in the Streptomyces enzyme, which is absent in the Aeromonas enzyme. Binding of Ca2+ enhances stability of the Streptomyces enzyme and modulates its activity and affinity towards substrates and inhibitors in a structure-dependent manner.

Creation and characterization of a new, non-redundant fragment data bank.

The success achieved for protein structure prediction of loop regions with insertions and deletions by knowledge-based methods depends on the quality of the underlying information, i.e. a fragment data bank as complete as possible is needed.

NMR spectroscopic evidence that helodermin, unlike other members of the secretin/VIP family of peptides, is substantially structured in water.

The structure in water and additionally in 50% trifluoroethanol (TFE) solution of helodermin, an amidated peptide consisting of 35 amino acids, was elucidated by 2D 1H NMR spectroscopy initially from H alpha chemical shifts and qualitative NOE data. Detailed structures were calculated from the quantitative NOE data which were used as distance restraints in molecular dynamics and energy minimization calculations. Regions of stable secondary structure were defined from the resulting final peptide conformations using a new fitting program that takes into account the summed RMS differences between all structures for short segments of 2-5 residues in length.

Similarities between protein 3-D structures.

A simple, new, systematic method has been developed to evaluate the structural similarity of proteins. Firstly, similar protein fragments of a definable length are detected, combined in pairs and superimposed. The fits are improved until a maximum number of C alpha atoms show a distance below a given threshold value.