Computational Pharmaceutical Chemistry and Molecular Informatics Group

Permanent URI for this collectionhttps://researchdata.hhu.de/handle/entry/76

Our research focusses on understanding, predicting, and modulating biomolecular interactions from an atomistic perspective.

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Browsing Computational Pharmaceutical Chemistry and Molecular Informatics Group by Author "Bonus, Michele"

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    SQLite file for TopCysteineDB: A Cysteinome-wide Database Integrating Structural and Chemoproteomics Data for Cysteine Ligandability Prediction
    (N/A, 2025-04) Bonus, Michele; Greb, Julian; Majmudar, Jaimeen D.; Boehm, Markus; Korczynska, Magdalena; Nazemi, Azadeh; Mathiowetz, Alan M.; Gohlke, Holger
    Development of targeted covalent inhibitors and covalent ligand-first approaches have emerged as a powerful strategy in drug design, with cysteines being attractive targets due to their nucleophilicity and relative scarcity. While structural biology and chemoproteomics approaches have generated extensive data on cysteine ligandability, these complementary data types remain largely disconnected. Here, we present TopCysteineDB, a comprehensive resource integrating structural information from the PDB with chemoproteomics data from activity-based protein profiling experiments. Analysis of the complete PDB yielded 264,234 unique cysteines, while the proteomics dataset encompasses 41,898 detectable cysteines across the human proteome. Using TopCovPDB, an automated classification pipeline complemented by manual curation, we identified 787 covalent cysteines and systematically categorized other functional roles, including metal-binding, cofactor-binding, and disulfide bonds. Mapping residue-wise structural information to sequence space enabled cross-referencing between structural and proteomics data, creating a unified view of cysteine ligandability. For TopCySPAL, a machine learning model was developed, integrating structural features and proteomics data, achieving strong predictive performance (AUROC: 0.964, AUPRC: 0.914) and robust generalization to novel cases. TopCysteineDB and TopCySPAL are freely accessible through a webinterface, TopCysteineDBApp (https://topcysteinedb.hhu.de/), designed to facilitate exploration of cysteine sites across the human proteome. The interface provides an interactive visualization featuring a color-coded mapping of chemoproteomics data onto cysteine site structures and the highlighting of identified peptide sequences. It offers customizable dataset downloads and ligandability predictions for user-provided structures. This resource advances targeted covalent inhibitor design by providing integrated access to previously dispersed data types and enabling systematic analysis and prediction of cysteine ligandability.
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    Uncoupling of voltage- and ligand-induced activation in HCN2 channels by glycine inserts v2
    (N/A, 2022) Sezin, Yüksel; Bonus, Michele; Pfleger, Christopher; Gohlke, Holger; Benndorf, Klaus; Kusch, Jana
    Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetramers that generate electrical rhythmicity in special brain neurons and cardiomyocytes. The channels are activated by membrane hyperpolarization. The binding of cAMP to the four available cyclic nucleotide-binding domains (CNBD) enhances channel activation. We analyzed in the present study the mechanism of how the effect of cAMP binding is transmitted to the pore domain (PD). Our strategy was to uncouple the C-linker (CL) from the channel core by inserting one to five glycine residues between the S6 gate and the A’-helix (constructs 1G to 5G). We quantified in full-length HCN2 channels the resulting functional effects of the inserted glycines by current activation as well as the structural dynamics and statics using molecular dynamics simulations and Constraint Network Analysis (CNA). We show functionally that already in 1G the cAMP effect on activation is lost and that with the exception of 3G and 5G the concentration-activation relationships are shifted to depolarized voltages with respect to HCN2. The strongest effect was found for 4G. Accordingly, the activation kinetics were accelerated by all constructs, again with the strongest effect in 4G. The simulations reveal that the average residue mobility of the CL and CNBD domains is increased in all constructs and that the junction between the S6 and A’-helix is turned into a flexible hinge, resulting in a destabilized gate in all constructs. Moreover, for 3G and 4G, there is a stronger downward displacement of the CL-CNBD than in HCN2 and the other constructs, resulting in an increased kink angle between S6 and A’-helix, which in turn loosens contacts between the S4-helix and the CL. This is suggested to promote a downward movement of the S4-helix, similar to the effect of hyperpolarization. In addition, exclusively in 4G, the selectivity filter in the upper pore region and parts of the S4-helix are destabilized. The results provide new insights into the intricate activation of HCN2 channels.