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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).

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., (© 2022. The Author(s).)

Computer-aided drug design methods such as docking, pharmacophore searching, 3D database searching, and the creation of 3D-QSAR models need conformational ensembles to handle the flexibility of small molecules. Here, we present Conformator, an accurate and effective knowledge-based algorithm for generating conformer ensembles. With 99.9% of all test molecules processed, Conformator stands out by its robustness with respect to input formats, molecular geometries, and the handling of macrocycles. With an extended set of rules for sampling torsion angles, a novel algorithm for macrocycle conformer generation, and a new clustering algorithm for the assembly of conformer ensembles, Conformator reaches a median minimum root-mean-square deviation (measured between protein-bound ligand conformations and ensembles of a maximum of 250 conformers) of 0.47 Å with no significant difference to the highest-ranked commercial algorithm OMEGA and significantly higher accuracy than seven free algorithms, including the RDKit DG algorithm. Conformator is freely available for noncommercial use and academic research.

We developed a cheminformatics pipeline for the fully automated selection and extraction of high-quality protein-bound ligand conformations from X-ray structural data. The pipeline evaluates the validity and accuracy of the 3D structures of small molecules according to multiple criteria, including their fit to the electron density and their physicochemical and structural properties. Using this approach, we compiled two high-quality datasets from the Protein Data Bank (PDB): a comprehensive dataset and a diversified subset of 4626 and 2912 structures, respectively. The datasets were applied to benchmarking seven freely available conformer ensemble generators: Balloon (two different algorithms), the RDKit standard conformer ensemble generator, the Experimental-Torsion basic Knowledge Distance Geometry (ETKDG) algorithm, Confab, Frog2 and Multiconf-DOCK. Substantial differences in the performance of the individual algorithms were observed, with RDKit and ETKDG generally achieving a favorable balance of accuracy, ensemble size and runtime. The Platinum datasets are available for download from http://www.zbh.uni-hamburg.de/platinum_dataset .