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.

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.

The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites.

G-protein-coupled receptors do not only feature the orthosteric pockets, where most endogenous agonists bind, but also a multitude of other allosteric pockets that have come into the focus as potential binding sites for synthetic modulators. Here, to better characterise such pockets, we investigate 557 GPCR structures by exhaustively docking small molecular probes in silico and converting the ensemble of binding locations to pocket-defining volumes. Our analysis confirms all previously identified pockets and reveals nine previously untargeted sites. In order to test for the feasibility of functional modulation of receptors through binding of a ligand to such sites, we mutate residues in two sites, in two model receptors, the muscarinic acetylcholine receptor M3 and ß2-adrenergic receptor. Moreover, we analyse the correlation of inter-residue contacts with the activation states of receptors and show that contact patterns closely correlating with activation indeed coincide with these sites.