SpaceGrow: efficient shape-based virtual screening of billion-sized combinatorial fragment spaces.

The growing size of make-on-demand chemical libraries is posing new challenges to cheminformatics. These ultra-large chemical libraries became too large for exhaustive enumeration. Using a combinatorial approach instead, the resource requirement scales approximately with the number of synthons instead of the number of molecules. This gives access to billions or trillions of compounds as so-called chemical spaces with moderate hardware and in a reasonable time frame. While extremely performant ligand-based 2D methods exist in this context, 3D methods still largely rely on exhaustive enumeration and therefore fail to apply. Here, we present SpaceGrow: a novel shape-based 3D approach for ligand-based virtual screening of billions of compounds within hours on a single CPU. Compared to a conventional superposition tool, SpaceGrow shows comparable pose reproduction capacity based on RMSD and superior ranking performance while being orders of magnitude faster. Result assessment of two differently sized subsets of the eXplore space reveals a higher probability of finding superior results in larger spaces highlighting the potential of searching in ultra-large spaces. Furthermore, the application of SpaceGrow in a drug discovery workflow was investigated in four examples involving G protein-coupled receptors (GPCRs) with the aim to identify compounds with similar binding capabilities and molecular novelty.

Database-Driven Identification of Structurally Similar Protein-Protein Interfaces.

Analyzing the similarity of protein interfaces in protein-protein interactions gives new insights into protein function and assists in discovering new drugs. Usually, tools that assess the similarity focus on the interactions between two protein interfaces, while sometimes we only have one predicted interface. Herein, we present PiMine, a database-driven protein interface similarity search. It compares interface residues of one or two interacting chains by calculating and searching tetrahedral geometric patterns of α-carbon atoms and calculating physicochemical and shape-based similarity. On a dedicated, tailor-made dataset, we show that PiMine outperforms commonly used comparison tools in terms of early enrichment when considering interfaces of sequentially and structurally unrelated proteins. In an application example, we demonstrate its usability for protein interaction partner prediction by comparing predicted interfaces to known protein-protein interfaces.

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. We extend the original algorithm by the capabilities to compute distributions for the TPSA, the number of rotatable bonds, and the occurrence of user-defined molecular structures in the form of SMARTS patterns. Furthermore, SpaceProp2 produces example molecules for every property bin, enabling a detailed interpretation of the distributions. We demonstrate SpaceProp2 on six established make-on-demand chemical fragment spaces as well as BICLAIM, the in-house fragment space of Boehringer Ingelheim. The possibility to search multiple SMARTS patterns simultaneously as well as the produced example molecules offers previously impossible insights into the composition of these vast combinatorial molecule collections, making it an ideal tool for the analysis and design of chemical fragment spaces.

SiteMine: Large-scale binding site similarity searching in protein structure databases.

Drug discovery and design challenges, such as drug repurposing, analyzing protein-ligand and protein-protein complexes, ligand promiscuity studies, or function prediction, can be addressed by protein binding site similarity analysis. Although numerous tools exist, they all have individual strengths and drawbacks with regard to run time, provision of structure superpositions, and applicability to diverse application domains. Here, we introduce SiteMine, an all-in-one database-driven, alignment-providing binding site similarity search tool to tackle the most pressing challenges of binding site comparison. The performance of SiteMine is evaluated on the ProSPECCTs benchmark, showing a promising performance on most of the data sets. The method performs convincingly regarding all quality criteria for reliable binding site comparison, offering a novel state-of-the-art approach for structure-based molecular design based on binding site comparisons. In a SiteMine showcase, we discuss the high structural similarity between cathepsin L and calpain 1 binding sites and give an outlook on the impact of this finding on structure-based drug design. SiteMine is available at https://uhh.de/naomi.

Redocking the PDB.

Molecular docking is a standard technique in structure-based drug design (SBDD). It aims to predict the 3D structure of a small molecule in the binding site of a receptor (often a protein). Despite being a common technique, it often necessitates multiple tools and involves manual steps. Here, we present the JAMDA preprocessing and docking workflow that is easy to use and allows fully automated docking. We evaluate the JAMDA docking workflow on binding sites extracted from the complete PDB and derive key factors determining JAMDA's docking performance. With that, we try to remove most of the bias due to manual intervention and provide a realistic estimate of the redocking performance of our JAMDA preprocessing and docking workflow for any PDB structure. On this large PDBScan22 data set, our JAMDA workflow finds a pose with an RMSD of at most 2 Å to the crystal ligand on the top rank for 30.1% of the structures. When applying objective structure quality filters to the PDBScan22 data set, the success rate increases to 61.8%. Given the prepared structures from the JAMDA preprocessing pipeline, both JAMDA and the widely used AutoDock Vina perform comparably on this filtered data set (the PDBScan22-HQ data set).

Full Modification Control over Retrosynthetic Routes for Guided Optimization of Lead Structures.

Synthesizability is essential for compounds designed in silico. Regardless, synthetic accessibility is often considered only as an afterthought in the design and optimization process. In addition, the trend with modern computer-aided drug design methods is going toward full automation and away from the possibility of incorporating user knowledge. With this work, we present the second major release of our software tool, Synthesia, for synthesis-aware lead structure modification, where the user's expertise is now fully utilized. A provided retrosynthetic route is used as a pathway to guide structural modifications that introduce desired structural changes in the target compound. Moreover, the approach allows the user to define the exact position or component in the retrosynthetic route, which should be modified, further integrating the user's expert knowledge. This paper describes the functionality of Synthesia, its basic concepts, and several application scenarios ranging from simple examples to a comparison of the effects of the different exchange functions to an analysis of a set of bioisosteric linker structures, highlighting potential synthetically feasible replacements.

Searching similar local 3D micro-environments in protein structure databases with MicroMiner.

The available protein structure data are rapidly increasing. Within these structures, numerous local structural sites depict the details characterizing structure and function. However, searching and analyzing these sites extensively and at scale poses a challenge. We present a new method to search local sites in protein structure databases using residue-defined local 3D micro-environments. We implemented the method in a new tool called MicroMiner and demonstrate the capabilities of residue micro-environment search on the example of structural mutation analysis. Usually, experimental structures for both the wild-type and the mutant are unavailable for comparison. With MicroMiner, we extracted $>255 \times 10^{6}$ amino acid pairs in protein structures from the PDB, exemplifying single mutations' local structural changes for single chains and $>45 \times 10^{6}$ pairs for protein-protein interfaces. We further annotate existing data sets of experimentally measured mutation effects, like $\Delta \Delta G$ measurements, with the extracted structure pairs to combine the mutation effect measurement with the structural change upon mutation. In addition, we show how MicroMiner can bridge the gap between mutation analysis and structure-based drug design tools. MicroMiner is available as a command line tool and interactively on the https://proteins.plus/ webserver.

School of cheminformatics in Latin America.

We report the major highlights of the School of Cheminformatics in Latin America, Mexico City, November 24-25, 2022. Six lectures, one workshop, and one roundtable with four editors were presented during an online public event with speakers from academia, big pharma, and public research institutions. One thousand one hundred eighty-one students and academics from seventy-nine countries registered for the meeting. As part of the meeting, advances in enumeration and visualization of chemical space, applications in natural product-based drug discovery, drug discovery for neglected diseases, toxicity prediction, and general guidelines for data analysis were discussed. Experts from ChEMBL presented a workshop on how to use the resources of this major compounds database used in cheminformatics. The school also included a round table with editors of cheminformatics journals. The full program of the meeting and the recordings of the sessions are publicly available at https://www.youtube.com/@SchoolChemInfLA/featured .

LifeSoaks: a tool for analyzing solvent channels in protein crystals and obstacles for soaking experiments.

Due to the structural complexity of proteins, their corresponding crystal arrangements generally contain a significant amount of solvent-occupied space. These areas allow a certain degree of intracrystalline protein flexibility and mobility of solutes. Therefore, knowledge of the geometry of solvent-filled channels and cavities is essential whenever the dynamics inside a crystal are of interest. Especially in soaking experiments for structure-based drug design, ligands must be able to traverse the crystal solvent channels and reach the corresponding binding pockets. Unsuccessful screenings are sometimes attributed to the geometry of the crystal packing, but the underlying causes are often difficult to understand. This work presents LifeSoaks, a novel tool for analyzing and visualizing solvent channels in protein crystals. LifeSoaks uses a Voronoi diagram-based periodic channel representation which can be efficiently computed. The size and location of channel bottlenecks, which might hinder molecular diffusion, can be directly derived from this representation. This work presents the calculated bottleneck radii for all crystal structures in the PDB and the analysis of a new, hand-curated data set of structures obtained by soaking experiments. The results indicate that the consideration of bottleneck radii and the visual inspection of channels are beneficial for planning soaking experiments.

PoseEdit: enhanced ligand binding mode communication by interactive 2D diagrams.

In this article, we present PoseEdit, a new, interactive frontend of the popular pose visualization tool PoseView. PoseEdit automatically produces high-quality 2D diagrams of intermolecular interactions in 3D binding sites calculated from ligands in complex with protein, DNA, and RNA. The PoseView diagrams have been improved in several aspects, most notably in their interactivity. Thanks to the easy-to-use 2D editor of PoseEdit, the diagrams are extensively editable and extendible by the user, can be merged with other diagrams, and even be created from scratch. A large variety of graphical objects in the diagram can be moved, rotated, selected and highlighted, mirrored, removed, or even newly added. Furthermore, PoseEdit enables a synchronized 2D-3D view of macromolecule-ligand complexes simplifying the analysis of structural features and interactions. The representation of individual diagram objects regarding their visualized chemical properties, like stereochemistry, and general graphical styles, like the color of interactions, can additionally be edited. The primary objective of PoseEdit is to support scientists with an enhanced way to communicate ligand binding mode information through graphical 2D representations optimized with the scientist's input in accordance with objective criteria and individual needs. PoseEdit is freely available on the ProteinsPlus web server ( https://proteins.plus ).

Binding Site Detection Remastered: Enabling Fast, Robust, and Reliable Binding Site Detection and Descriptor Calculation with DoGSite3.

Binding site prediction on protein structures is a crucial step in early phase drug discovery whenever experimental or predicted structure models are involved. DoGSite belongs to the widely used tools for this task. It is a grid-based method that uses a Difference-of-Gaussian filter to detect cavities on the protein surface. We recently reimplemented the first version of this method, released in 2010, focusing on improved binding site detection in the presence of ligands and optimized parameters for more robust, reliable, and fast predictions and binding site descriptor calculations. Here, we introduce the new version, DoGSite3, compare it to its predecessor, and re-evaluate DoGSite on published data sets for a large-scale comparative performance evaluation.

Modeling with Alternate Locations in X-ray Protein Structures.

In many molecular modeling applications, the standard procedure is still to handle proteins as single, rigid structures. While the importance of conformational flexibility is widely known, handling it remains challenging. Even the crystal structure of a protein usually contains variability exemplified in alternate side chain orientations or backbone segments. This conformational variability is encoded in PDB structure files by so-called alternate locations (AltLocs). Most modeling approaches either ignore AltLocs or resolve them with simple heuristics early on during structure import. We analyzed the occurrence and usage of AltLocs in the PDB and developed an algorithm to automatically handle AltLocs in PDB files enabling all structure-based methods using rigid structures to take the alternative protein conformations described by AltLocs into consideration. A respective software tool named AltLocEnumerator can be used as a structure preprocessor to easily exploit AltLocs. While the amount of data makes it difficult to show impact on a statistical level, handling AltLocs has a substantial impact on a case-by-case basis. We believe that the inspection and consideration of AltLocs is a very valuable approach in many modeling scenarios.

Navigating large chemical spaces in early-phase drug discovery.

The size of actionable chemical spaces is surging, owing to a variety of novel techniques, both computational and experimental. As a consequence, novel molecular matter is now at our fingertips that cannot and should not be neglected in early-phase drug discovery. Huge, combinatorial, make-on-demand chemical spaces with high probability of synthetic success rise exponentially in content, generative machine learning models go hand in hand with synthesis prediction, and DNA-encoded libraries offer new ways of hit structure discovery. These technologies enable to search for new chemical matter in a much broader and deeper manner with less effort and fewer financial resources. These transformational developments require new cheminformatics approaches to make huge chemical spaces searchable and analyzable with low resources, and with as little energy consumption as possible. Substantial progress has been made in the past years with respect to computation as well as organic synthesis. First examples of bioactive compounds resulting from the successful use of these novel technologies demonstrate their power to contribute to tomorrow's drug discovery programs. This article gives a compact overview of the state-of-the-art.

Galileo: Three-dimensional searching in large combinatorial fragment spaces on the example of pharmacophores.

Fragment spaces are an efficient way to model large chemical spaces using a handful of small fragments and a few connection rules. The development of Enamine's REAL Space has shown that large spaces of readily available compounds may be created this way. These are several orders of magnitude larger than previous libraries. So far, searching and navigating these spaces is mostly limited to topological approaches. A way to overcome this limitation is optimization via metaheuristics which can be combined with arbitrary scoring functions. Here we present Galileo, a novel Genetic Algorithm to sample fragment spaces. We showcase Galileo in combination with a novel pharmacophore mapping approach, called Phariety, enabling 3D searches in fragment spaces. We estimate the effectiveness of the approach with a small fragment space. Furthermore, we apply Galileo to two pharmacophore searches in the REAL Space, detecting hundreds of compounds fulfilling a HSP90 and a FXIa pharmacophore.

Visualizing Generic Reaction Patterns.

Reaction schemes for organic molecules play a crucial role in modern in silico drug design processes. In contrast to the classical drawn reaction diagrams, computational chemists prefer SMARTS based line notations due to a substantially increased expressiveness and precision. They are used to search databases, calculate synthesizability, generate new molecules, or simulate novel reactions. Working with computer-readable representations of reaction schemes can be challenging due to the complexity of the features to be represented. Line representations of reaction schemes can often be cryptic, even to experienced users. To simplify the work with Reaction SMARTS for synthetic, computational, and medicinal chemists, we introduce a visualization technique for reaction schemes and provide a respective tool, called ReactionViewer. ReactionViewer is able to convert reaction schemes encoded as Reaction SMILES, Reaction SMARTS, or SMIRKS into a visual representation. The visualization technique is based on the concept of structure diagrams and follows IUPAC's "Compendium of Chemical Terminology" definition of chemical reaction equations for the reaction symbols. We demonstrate the applicability of the method using two data sets of organic synthesis reaction schemes taken from recent publications. We discuss various properties of the visualization and highlight its readability and interpretability.

FastGrow: on-the-fly growing and its application to DYRK1A.

Fragment-based drug design is an established routine approach in both experimental and computational spheres. Growing fragment hits into viable ligands has increasingly shifted into the spotlight. FastGrow is an application based on a shape search algorithm that addresses this challenge at high speeds of a few milliseconds per fragment. It further features a pharmacophoric interaction description, ensemble flexibility, as well as geometry optimization to become a fully fledged structure-based modeling tool. All features were evaluated in detail on a previously reported collection of fragment growing scenarios extracted from crystallographic data. FastGrow was also shown to perform competitively versus established docking software. A case study on the DYRK1A kinase, using recently reported new chemotypes, illustrates FastGrow's features in practice and its ability to identify active fragments. FastGrow is freely available to the public as a web server at https://fastgrow.plus/ and is part of the SeeSAR 3D software package.

Synthesis-Aware Generation of Structural Analogues.

In modern drug design, one of the main issues is the optimization of an initial lead structure toward a drug candidate by modifying specific properties in the desired direction. The synthetic feasibility of the target structure is often neglected during this process, resulting in structures with low or suboptimal synthetic accessibility. In this work, we present a novel approach for synthesis-aware lead optimization called Synthesia. In contrast to the traditional approaches, Synthesia integrates the preservation of the synthesizability of the target structure into the lead structure modification process. Synthesia is able to create structural diversity for a lead structure that matches user-defined molecular properties without losing the applicability of a particular synthetic pathway. The methodology is validated by demonstrating that Synthesia is capable of providing structural analogues of DrugBank compounds that meet generic modification goals and maintain their synthetic pathways. In addition, Synthesia is used to cluster compounds from two different patent structure series (CDK7, Daurismo) according to their compatibility with the same synthetic pathways, maximizing the synthetic efficiency and providing an initial estimation of the effort of synthesizing the entire series. Altogether, we demonstrate Synthesia's ability to modify compound properties while maintaining in silico synthesizability.

Calculating and Optimizing Physicochemical Property Distributions of Large Combinatorial Fragment Spaces.

The distributions of physicochemical property values, like the octanol-water partition coefficient, are routinely calculated to describe and compare virtual chemical libraries. Traditionally, these distributions are derived by processing each member of a library individually and summarizing all values in a distribution. This process becomes impractical when operating on chemical spaces which surpass billions of compounds in size. In this work, we present a novel algorithmic method called SpaceProp for the property distribution calculation of large nonenumerable combinatorial fragment spaces. The novel method follows a combinatorial approach and is able to calculate physicochemical property distributions of prominent spaces like Enamine's REAL Space, WuXi's GalaXi Space, and OTAVA's CHEMriya Space for the first time. Furthermore, we present a first approach of optimizing property distributions directly in combinatorial fragment spaces.

Exploration of Ultralarge Compound Collections for Drug Discovery.

Designing new medicines more cheaply and quickly is tightly linked to the quest of exploring chemical space more widely and efficiently. Chemical space is monumentally large, but recent advances in computer software and hardware have enabled researchers to navigate virtual chemical spaces containing billions of chemical structures. This review specifically concerns collections of many millions or even billions of enumerated chemical structures as well as even larger chemical spaces that are not fully enumerated. We present examples of chemical libraries and spaces and the means used to construct them, and we discuss new technologies for searching huge libraries and for searching combinatorially in chemical space. We also cover space navigation techniques and consider new approaches to de novo drug design and the impact of the "autonomous laboratory" on synthesis of designed compounds. Finally, we summarize some other challenges and opportunities for the future.