Statistical Analysis and Prediction of Covalent Ligand Targeted Cysteine Residues

Weilin Zhang, Jianfeng Pei, and Luhua Lai
J. Chem. Inf. Model., Just Accepted Manuscript
DOI: 10.1021/acs.jcim.7b00163
Publication Date (Web): May 16, 2017

Targeted covalent compounds or drugs have good potency as they can bind to a specific target for a long time with low doses. Most currently known covalent ligands were discovered by chance or by modifying existing non-covalent compounds to make them covalently attached to a nearby reactive residue. Computational methods for novel covalent ligand binding prediction are highly demanded. We performed statistical analysis on protein complexes with covalent ligands attached to cysteine residues. We found that covalent modified cysteine residues have unique features compared to those not attached to covalent ligands, including lower pKa, higher exposure and higher ligand binding affinity. SVM models were built to predict cysteine residues suitable for covalent ligand design with prediction accuracy of 0.73. Given a protein structure, our method can be used to automatically detect druggable Cys residues for covalent ligand design, which is especially useful for identifying novel binding sites for covalent allosteric regulating ligand design.

Direct 11CN-Labeling of Unprotected Peptides via Palladium-Mediated Sequential Cross-Coupling Reactions

Wenjun Zhao†‡∥, Hong Geun Lee§∥, Stephen L. Buchwald*§, and Jacob M. Hooker*†‡ 

† Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States

‡ Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States

§ Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

A practical procedure for 11CN-labeling of unprotected peptides has been developed. The method was shown to be highly chemoselective for cysteine over other potentially nucleophilic residues, and the radiolabeled products were synthesized and purified in less than 15 min. Appropriate for biomedical applications, the method could be used on an extremely small scale (20 nmol) with a high radiochemical yield. The success of the protocol stems from the use of a Pd-reagent based on a dihaloarene, which enables direct “nucleophile–nucleophile” coupling of the peptide and [11C]cyanide by temporal separation of nucleophile addition.

J. Am. Chem. Soc., Article ASAP

DOI: 10.1021/jacs.7b02761

Publication Date (Web): May 15, 2017

Thiol Specific and Tracelessly Removable Bioconjugation via Michael Addition to 5-Methylene Pyrrolones

Yingqian Zhang†⊥, Xiaoping Zhou†⊥, Yonghui Xie†, Marc M. Greenberg§ , Zhen Xi†‡, and Chuanzheng Zhou

† State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
§ Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States

J. Am. Chem. Soc., 2017, 139 (17), 6146–6151
DOI: 10.1021/jacs.7b00670

Chemistry World: Drugs, the permanent way

Exceptions to a long-held rule against chemically bonding to biological targets are powering new cancer medicines, finds Andy Extance

https://www.chemistryworld.com/feature/covalent-inhibitor-drugs/2500494.article

Determining cysteines available for covalent inhibition across the human kinome

Zheng Zhao, Qingsong Liu, Spencer Bliven, Lei Xie, and Philip E. Bourne

J. Med. Chem., 2017, 60 (7), pp 2879–2889

DOI: 10.1021/acs.jmedchem.6b01815

Covalently bound protein kinase inhibitors have been frequently designed to target non-catalytic cysteines at the ATP binding site. Thus, it is important to know if a given cysteine can form a covalent bond. Here we combine a function-site interaction fingerprint method and DFT calculations to determine the potential of cysteines to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site cysteine dataset was assembled. The orientation of the cysteine thiol group indicates which cysteines can potentially form covalent bonds. These covalent inhibitor accessible cysteines are located within five regions: P-loop, roof of pocket, front pocket, catalytic-2 of the catalytic loop and DFG-3 close to the DFG peptide. In an independent test set, these cysteines covered 95% of covalent kinase inhibitors. This study provides new insights into cysteine reactivity and preference which is important for the prospective development of covalent kinase inhibitors.

Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells

Joel D. Federspiel, Simona G. Codreanu, Sandeep Goyal, Matthew E. Albertolle, Eric Lowe, Juli Teague, Hansen Wong, F. Peter Guengerich and Daniel C. Liebler

http://www.mcponline.org/content/15/10/3233.short

Ligand and Target Discovery by Fragment-Based Screening in Human Cells

Christopher G. Parker, Andrea Galmozzi, Yujia Wang, Bruno E. Correia, Kenji Sasaki, Christopher M. Joslyn, Arthur S. Kim, Cullen L. Cavallaro, R. Michael Lawrence, Stephen R. Johnson, Iñigo Narvaiza, Enrique Saez, Enrique Saez,Enrique Saez, Benjamin F. Cravatt6, Benjamin F. Cravatt

DOI: 10.1016/j.cell.2016.12.029