@article{GorgullaNigamKoopetal.2023, author = {Gorgulla, Christoph and Nigam, AkshatKumar and Koop, Matt and Selim {\c{C}}{\i}naroğlu, S{\"u}leyman and Secker, Christopher and Haddadnia, Mohammad and Kumar, Abhishek and Malets, Yehor and Hasson, Alexander and Li, Minkai and Tang, Ming and Levin-Konigsberg, Roni and Radchenko, Dmitry and Kumar, Aditya and Gehev, Minko and Aquilanti, Pierre-Yves and Gabb, Henry and Alhossary, Amr and Wagner, Gerhard and Aspuru-Guzik, Al{\´a}n and Moroz, Yurii S. and Fackeldey, Konstantin and Arthanari, Haribabu}, title = {VirtualFlow 2.0 - The Next Generation Drug Discovery Platform Enabling Adaptive Screens of 69 Billion Molecules}, journal = {bioRxiv}, doi = {10.1101/2023.04.25.537981}, year = {2023}, language = {en} } @article{CoomberChewleSeckeretal.2025, author = {Coomber, Celvic and Chewle, Surahit and Secker, Christopher and Fackeldey, Konstantin and Weber, Marcus and Winkelmann, Stefanie and Sch{\"u}tte, Christof and Sunkara, Vikram}, title = {Investigating Endogenous Opioids Unravels the Mechanisms Behind Opioid-Induced Constipation, a Mathematical Modeling Approach}, volume = {26}, journal = {International Journal of Molecular Sciences}, number = {13}, doi = {10.3390/ijms26136207}, year = {2025}, abstract = {Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC.}, language = {en} } @article{SeckerFackeldeyWeberetal.2023, author = {Secker, Christopher and Fackeldey, Konstantin and Weber, Marcus and Ray, Sourav and Gorgulla, Christoph and Sch{\"u}tte, Christof}, title = {Novel multi-objective affinity approach allows to identify pH-specific μ-opioid receptor agonists}, volume = {15}, journal = {Journal of Cheminformatics}, doi = {10.1186/s13321-023-00746-4}, year = {2023}, abstract = {Opioids are essential pharmaceuticals due to their analgesic properties, however, lethal side effects, addiction, and opioid tolerance are extremely challenging. The development of novel molecules targeting the μ-opioid receptor (MOR) in inflamed, but not in healthy tissue, could significantly reduce these unwanted effects. Finding such novel molecules can be achieved by maximizing the binding affinity to the MOR at acidic pH while minimizing it at neutral pH, thus combining two conflicting objectives. Here, this multi-objective optimal affinity approach is presented, together with a virtual drug discovery pipeline for its practical implementation. When applied to finding pH-specific drug candidates, it combines protonation state-dependent structure and ligand preparation with high-throughput virtual screening. We employ this pipeline to characterize a set of MOR agonists identifying a morphine-like opioid derivative with higher predicted binding affinities to the MOR at low pH compared to neutral pH. Our results also confirm existing experimental evidence that NFEPP, a previously described fentanyl derivative with reduced side effects, and recently reported β-fluorofentanyls and -morphines show an increased specificity for the MOR at acidic pH when compared to fentanyl and morphine. We further applied our approach to screen a >50K ligand library identifying novel molecules with pH-specific predicted binding affinities to the MOR. The presented differential docking pipeline can be applied to perform multi-objective affinity optimization to identify safer and more specific drug candidates at large scale.}, language = {en} }