Applications to Chemical Biology and Pharmaceutical Sciences

G-protein coupled receptors (GPCRs)

We have been engaged in various drug design projects targeting G-protein coupled receptors (GPCRs) and downstream signal transduction pathways. Using our own QSAR methods, we have been involved in the design of specific lead compounds, both in industrial and academic collaborations, for a series of different GPCRs, such as neurokinin-1 or chemokine-3 receptors. In collaborations with Prof. Nichols (Synthetic Medicinal Chemistry) and Prof. Watts (Molecular Pharmacology), we have used docking, MD simulations and free energy calculations for the design of chroman analogous, as well as dihydrexidine and doxanthrin derivatives as selective dopamine-1 ligands. As part of these collaborations, we also investigated the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonists. In collaboration with Prof. van Rjin (Molecular Pharmacology) and Prof. Cushman (Synthetic Medicinal Chemistry), we currently design functionally selective δ-opioid receptor modulators for treating alcohol abuse and chronic pain. A recent collaboration with Prof. Watts allowed us to identify a new allosteric modulator targeting adenylyl cyclase 2.This project has been extended targeting adenylyl
cyclase 1.

Rana, N.; Conley, J.M.; Soto-Velasquez, M.; León, F.; Cutler, S.J.; Watts, V.J.; Lill, M.A. Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor. J. Chem. Inf. Model. 57, 2017, 322-334.

Juncosa, J.I.; Hansen, M.; Bonner, L.A.; Cueva, J.P.; Maglathlin, R.; McCorvy, J.D.; Marona-Lewicka, D.; Lill, M.A.; Nichols, D.E. Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT 2A serotonin receptor agonist ligands. ACS Chem. Neuro., 4, 2013, 96-109.

Cueva, J.P.; Gallardo-Godoy, A.; Juncosa, J.I.; Vidi, P.A.; Lill, M.A.; Watts, V.J.; Nichols, D.E. Probing the Steric Space at the Floor of the D(1) Dopamine Receptor Orthosteric Binding Domain: 7α-, 7β-, 8α-, and 8β-Methyl Substituted Dihydrexidine Analogues. J. Med. Chem., 54, 2011, 5508-5521.

Vedani, A.; Dobler M.; Dollinger H.; Hasselbach, K.-M.; Birke F; Lill, M.A. Novel ligands for the chemokine receptor-3 (CCR3): A receptor-modeling study based on 5D–QSAR. J. Med. Chem. 48, 2005, 1515-1527


Nuclear receptors

Nuclear receptors are ligand-inducible transcription factors that play an essential role in a multitude of physiological processes as well as diseases, rendering them attractive targets for selective modulation. They share a common helical architecture with high conservation of various regions of the protein. Our group has been engaged in various collaborative projects investigating the difference between nuclear receptor antagonists and agonists, the mechanism and selectivity of nuclear receptor drug compounds, and their potential for drug-drug interactions in a context of both drug design and toxicity prediction.

Nuclear receptors
TOC-2-2

Wahl, J. und Smieško, M. (2018) «Endocrine Disruption at the Androgen Receptor: Employing Molecular Dynamics and Docking for Improved Virtual Screening and Toxicity Prediction», Int.J. Mol. Sci., 19(6), 1784.

Sharifi, N.; Hamel, E.; Lill, M.A.; Risbood, P.; Kane, C.T. Jr.; Hossain, M.T.; Dalton, J.; Farrar, W.L. A bifunctional colchicinoid that binds the androgen receptor. Mol. Cancer Ther. 6, 2007, 2328-2336.


Drug Metabolism

We developed and used computational methods for the prediction of drug metabolism by cytochrome P450 enzymes in collaboration with Eli Lilly. Our group also investigates the access of ligands to the occluded active site of cytochrome P450 enzymes. By the use of computational methodology such as long-scale atomistic molecular dynamics simulations, we can gain insight into the transport mechanism of ligands with the aim to improve predictions of CYP binders. This is especially relevant, since CYP2D6 is subject to a genetic polymorphism that affects the interindividual metabolic performance. In our simulations, we include biological membranes and protein interaction partners to closely mimic the natural environment of the enzyme.

Drug Metabilism

Fischer, A., Don, C. G. und Smieško, M. (2018) «Molecular Dynamics Simulations Reveal Structural Differences among Allelic Variants of Membrane-Anchored Cytochrome P450 2D6», J. Chem. Inf. Model., 58(9), 1962-1975.

Don, C. G. und Smieško, M. (2018) «Out-compute drug side effects: Focus on cytochrome P450 2D6 modeling», Wiley Interdisciplinary Reviews: Computational Molecular Science. Wiley, S. e1366. doi: 10.1002/wcms.1366.

Kingsley, L.J.; Wilson, G.L.; Essex, M.E.; Lill, M.A.* Combining Structure- and Ligand-Based Approaches to Improve Site of Metabolism Prediction in CYP2C9 Substrates. Pharm. Res. 32, 2015, 986-1001.

Kingsley, L.J., Lill, M.A. Ensemble generation and the influence of protein flexibility on geometric tunnel prediction in cytochrome P450 enzymes. PLoS One 9, 2014, e99408.


Carbohydrate-Interacting Targets

Our group has a long term experience with modeling carbohydrate-protein interactions. Since 2006 we have been closely collaborating with the group of Prof. Beat Ernst, focused on the development of carbohydrate mimics for various targets including E- and P-selectin, FimH and Pap-G adhesin using a large variety of modeling methods. We use quantum chemical calculations on structural fragments and oligomers essential for establishing structure-activity relationships and design automated tools for prediction of physicochemical properties relevant for ADME profiling. In several projects we applied flexible docking and Molecular Dynamics simulations to elucidate the conformational properties and characteristic interaction patterns of lectins, carbohydrates and their complexes. Additionally, our carbohydrate research was supported by the SNF grant focused on exploring carbohydrate conformational preference in the gas, micro-hydrated and bulk solvent phases (SNF/Lead Agency Grant Nr. 200021L_157170). Our group co-authored several research papers in peer-review journals and contributed to two international patents on carbohydrate mimics (WO2015109049 A1, WO2017205269 A1).

Schönemann W, Cramer J, Mühlethaler T, Fiege B, Silbermann M, Rabbani S, Dätwyler P, Zihlmann P, Jakob RP, Sager CP, Smieško M, Schwardt O, Maier T, Ernst B: Improvement of Aglycone π‐Stacking Yields Nanomolar to Sub‐nanomolar FimH Antagonists. ChemMedChem. (2019), 14, 749-757.

Navarra G, Zihlmann P, Jakob R.P, Stangier K, Preston R.C, Rabbani S, Smieško M, Wagner B, Maier T, Ernst B: Carbohydrate-Lectin Interactions: An Unexpected Contribution to Affinity. Chembiochem. (2017), 18(6), 539-544.

Pang L, Bezençon J, Kleeb S, Rabbani S, Sigl A, Smieško M, Sager CP, Eris D, Schwardt O, Ernst B: FimH antagonists–solubility vs. permeability. Carbohydrate Chemistry (2016), 248-273.

Ernst B, Kleeb S, Pang L, Mayer K, Eris D, Sigl A, Zihlmann P, Preston R, Sharpe T, Jakob, R, Abgottspon D, Hutter A, Scharenberg M, Jiang X, Navarra G, Rabbani S,  Smieško M,  Lüdin N, Bezencon J, Schwardt O, Maier T: FimH Antagonists: Bioisosteres to Improve the in Vitro and in Vivo PK/PD Profile. J. Med. Chem  (2015), 58(5), 2221-2239.

Zierke M, Smieško M, Rabbani S, Aeschbacher TH, Cutting B, Allain FH-T, Schubert M, Ernst B: Stabilization of branched oligosaccharides: Lewisx benefits from a nonconventional C-H...O hydrogen bond. J. Am. Chem. Soc. (2013), 135 (36), 13464-13472.


Additional Collaborations

Other past and ongoing collaborative projects include the design of compounds targeting cyclooxygenases, isoprenylcysteine carboxyl methyltransferase, proliferating cell nuclear antigen, ion channels, deubiquitinases and phosphatases.

Wang, Y.; Tang, S.; Harvey, K. E.; Salyer, A. E.; Li, T. A.; Rantz, E. K.; Lill, M. A., Hockerman, G. H. Molecular Determinants of the Differential Modulation of Cav1.2 and Cav1.3 by Nifedipine and FPL 64176. Mol. Pharmacol. 94, 2018, 973-983.

Pedley, A.M.; Lill, M.A.; Davisson, V.J. Flexibility of PCNA-protein interface accommodates differential binding partners. PLoS One 9, 2014, e102481.

Morrow, M.E.; Kim, M.I.; Ronau, J.A.; Sheedlo, M.J.; White, R.R.; Chaney, J.; Paul, L.N.; Lill, M.A.; Artavanis-Tsakonas, K.; Das, C. Stabilization of an Unusual Salt Bridge in Ubiquitin by the Extra C-Terminal Domain of the Protease-Associated Deubiquitinase UCH37 as a Mechanism of Its Exo Specificity. Biochemistry 52, 2013, 3564-3578.

Jiang, Q.*; Yin, X.; Lill, M.A.; Danielson, M.L.; Freiser, H.; Huang, J. Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc. Natl. Acad. Sci., 105, 2008, 20464-20469.