@article{MTMT:32756662, title = {Electrophilic warheads in covalent drug discovery: an overview}, url = {https://m2.mtmt.hu/api/publication/32756662}, author = {Péczka, Nikolett and Orgován, Zoltán and Ábrányi-Balogh, Péter and Keserű, György Miklós}, doi = {10.1080/17460441.2022.2034783}, journal-iso = {EXPERT OPIN DRUG DIS}, journal = {EXPERT OPINION ON DRUG DISCOVERY}, volume = {17}, unique-id = {32756662}, issn = {1746-0441}, year = {2022}, eissn = {1746-045X}, pages = {413-422} } @article{MTMT:32544488, title = {Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads}, url = {https://m2.mtmt.hu/api/publication/32544488}, author = {Kollár, Levente and Gobec, Martina and Proj, Matic and Smrdel, Lara and Knez, Damijan and Imre, Timea and Gömöry, Ágnes and Petri, László and Ábrányi-Balogh, Péter and Csányi, Dorottya and Ferenczy, György and Gobec, Stanislav and Sosič, Izidor and Keserű, György Miklós}, doi = {10.3390/cells10123431}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {10}, unique-id = {32544488}, abstract = {Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.}, year = {2021}, eissn = {2073-4409}, orcid-numbers = {Kollár, Levente/0000-0001-9679-3735; Proj, Matic/0000-0003-4043-9686; Knez, Damijan/0000-0001-9917-1384; Gömöry, Ágnes/0000-0001-5216-0135; Petri, László/0000-0001-9881-5096; Ferenczy, György/0000-0002-5771-4616; Gobec, Stanislav/0000-0002-9678-3083; Sosič, Izidor/0000-0002-3370-4587} } @article{MTMT:31294506, title = {Cysteine specific bioconjugation with benzyl isothiocyanates}, url = {https://m2.mtmt.hu/api/publication/31294506}, author = {Petri, László and Szijj, Péter A. and Kelemen, Ádám and Imre, Timea and Gömöry, Ágnes and Lee, Maximillian T. W. and Hegedűs, Krisztina and Ábrányi-Balogh, Péter and Chudasama, Vijay and Keserű, György Miklós}, doi = {10.1039/D0RA02934C}, journal-iso = {RSC ADV}, journal = {RSC ADVANCES}, volume = {10}, unique-id = {31294506}, issn = {2046-2069}, year = {2020}, eissn = {2046-2069}, pages = {14928-14936}, orcid-numbers = {Petri, László/0000-0001-9881-5096; Gömöry, Ágnes/0000-0001-5216-0135} } @article{MTMT:3401463, title = {Comparative Evaluation of Covalent Docking Tools}, url = {https://m2.mtmt.hu/api/publication/3401463}, author = {Scarpino, Andrea and Ferenczy, György and Keserű, György Miklós}, doi = {10.1021/acs.jcim.8b00228}, journal-iso = {J CHEM INF MODEL}, journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING}, volume = {58}, unique-id = {3401463}, issn = {1549-9596}, abstract = {Increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity of covalent inhibitors. Here we compare the performance of six covalent docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE, for reproducing experimental binding modes in an unprecedently large and diverse set of covalent complexes. It was found that 40-60% of the top scoring ligand poses are within 2.0 Å RMSD from the experimental binding mode. This rate showed program dependent increase and achieved 50-90% when the best RMSD among the top ten scoring poses was considered. This performance is comparable to that of noncovalent docking tools and therefore suggests that anchoring the ligand does not necessarily improve the accuracy of the prediction. The effect of various ligand and protein features on the docking performance was investigated. At the level of warhead chemistry, higher success rate was found for Michael additions, nucleophilic additions and nucleophilic substitutions than for ring opening reactions and disulfide formation. Increasing ligand size and flexibility generally affects pose predictions unfavorably, although AutoDock4, FITTED, and ICM-Pro were found to be less sensitive up to 35 heavy atoms. Increasing the accessibility of the target cysteine tends to result in improved binding mode predictions. Docking programs show protein dependent performance suggesting a target-dependent choice of the optimal docking tool. It was found that noncovalent docking into Cys/Ala mutated proteins by ICM-Pro and Glide reproduced experimental binding modes with only slightly lower performance and at a significantly lower computational expense than covalent docking did. Overall, our results highlight the key factors influencing the docking performance of the investigated tools and they give guidelines for selecting the optimal combination of warheads, ligands, and tools for the system investigated. Results also identify the most important aspects to be considered for developing improved protocols for docking and virtual screening of covalent ligands. Copyright © 2018 American Chemical Society.}, keywords = {PROTEINS; LIGANDS; SULFUR COMPOUNDS; Forecasting; amino acids; binding energy; Addition reactions; NUCLEOPHILIC SUBSTITUTIONS; Virtual screening; Michael additions; Ring opening reaction; Computational expense; Optimal combination; Nucleophilic additions; Comparative evaluations}, year = {2018}, eissn = {1549-960X}, pages = {1441-1458}, orcid-numbers = {Ferenczy, György/0000-0002-5771-4616} }