Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the ...formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently. In contrast, we suggest that the reactive warhead itself should be tailored to the reactivity of the specific cysteine being targeted, and we describe a strategy to achieve this goal. Here, we have extended and systematically explored the available organic chemistry toolbox and characterized a large number of warheads representing different chemistries. We demonstrate that in addition to the common Michael addition, there are other nucleophilic addition, addition-elimination, nucleophilic substitution and oxidation reactions suitable for specific covalent protein modification. Importantly, we reveal that warheads for these chemistries impact the reactivity and specificity of covalent fragments at both protein and proteome levels. By integrating surrogate reactivity and selectivity models and subsequent protein assays, we define a road map to help enable new or largely unexplored covalent chemistries for the optimization of cysteine targeting inhibitors.
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•A broad library of cysteine targeting warheads was explored and characterized.•Diverse chemical reactions are suitable for specific covalent protein modification.•Warheads impact the reactivity and specificity of covalent fragments.•A road map for the optimization of cysteine targeting inhibitors is proposed.
Drug discovery efforts for new covalent inhibitors have drastically increased in the last few years. The binding mechanism of covalent compounds entails the formation of a chemical bond between their ...electrophilic warhead group and the protein of interest. The use of moderately reactive warheads targeting nonconserved nucleophilic residues can improve the affinity and selectivity profiles of covalent binders as compared to their non-covalent analogs. Recent advances have also enabled their use as chemical probes to disclose novel and also less tractable targets. Increasing interest in covalent drug discovery prompted the development of new computational tools, including covalent docking methods, that are available to predict the binding mode and affinity of covalent ligands. These tools integrate conventional non-covalent docking and scoring schemes by modeling the newly formed covalent bond and the interactions occurring at the reaction site. In this review, we provide a thorough analysis of state-of-the-art covalent docking programs by highlighting their main features and current limitations. Focusing on the implemented algorithms, we show the differences in handling the formation of the new covalent bond and their relative impact on the prediction. This analysis provides a comprehensive overview of the current technology and suggests future improvements in computer-aided covalent drug design. Finally, discussing successful retrospective and prospective covalent docking-based virtual screening applications, we intend to identify best practices for the drug discovery community.
Undocumented Scarpino, Andrea; Riekki, Ronald
03/2019
eBook
Focusing on contemporary issues, this text showcases a large collection of regional poets laureate writing on subjects critical to understanding social justice as it relates to the Great Lakes ...region.Undocumented: Great Lakes Poets Laureate on Social Justice includes writing by seventy-eight poets who truly represent the diversity of the Great Lakes region, including Rita Dove, Marvin Bell, Crystal Valentine, Kimberly Blaeser, Mary Weems, Karen Kovacik, Wendy Vardaman, Zora Howard, Carla Christopher, Meredith Holmes, Karla Huston, Joyce Sutphen, and Laren McClung, among others. City, state, and national poets laureate with ties to Illinois, Indiana, Michigan, Minnesota, New York, Ohio, Ontario, Pennsylvania, and Wisconsin appear in these pages, organized around themes from the Southern Poverty Law Center's "Ten Ways to Fight Hate: A Community Response Guide," calling on readers to act on behalf of victims of social injustice.
Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening ...cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.
Comparative Evaluation of Covalent Docking Tools Scarpino, Andrea; Ferenczy, György G; Keserű, György M
Journal of chemical information and modeling,
07/2018, Letnik:
58, Številka:
7
Journal Article
Recenzirano
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.
Through the last decades, drug discovery has benefited from breakthrough innovations made in all of the branches of this interdisciplinary field. A deeper understanding of pathophysiological ...conditions, together with technological advances pushing the boundaries of life sciences, have fueled the groundbreaking work that led to the development of several new drugs for the treatment of a vast range of diseases. Lately, one of the most expanding research fields is represented by covalent drug discovery, as indicated by the increasing number of citations referring to covalent inhibitors observed through the years (Figure 1). Here, an overview will be given to highlight their main features, advantages and applications, as well as the challenges faced in the rational design of compounds binding covalently to pharmaceutically relevant targets.1.1. Covalent drugs: binding mechanism and historical notesCovalent drugs typically exert their functional activity by covalently modifying the protein target at nucleophilic residues located nearby the active site or in allosteric pockets. The process involves the formation of new chemical bonds with the electrophilic moiety of the compound, also known as the “warhead” group. It is worth noting that most of covalent drugs were found by serendipity in phenotypic screens, while the mechanism of action was disclosed only after their approval. Following an initial skepticism, remarkable efforts have been made by academic and industrial players to revisit the importance of covalent drugs, by recognizing their factual presence on the market and establishing new principles for their rational design. Indeed, several covalent drugs acting on a broad scope of molecular targets have been approved by the US Food and Drug Administration (FDA). Among them, aspirin, penicillin, omeprazoleand clopidogrel 8 surely represent the most successful examples also in terms of target patient population reached, although many others were shown to be highly effective in treating life-impairing conditions. It is known that around 33% of enzymes with available marketed drugs have at least one representative drug acting through a mechanism based on covalent binding , but also other target classes were found to be modifiable (e.g., clopidogrel acts on a G protein-coupled receptor). Despite this, developments in the field were initially hindered by the risks of off-target labeling, generation of highly reactive metabolites and potential idiosyncratic reactions arising from the use of hyper-reactive and/or non-selective covalent binders. However, it was shown that this risk is rare and dependent on the drugs’ daily dose rather than on its mechanism. The recent findings, together with the introduction of guidelines for the design of potent and safe targeted covalent inhibitors (TCIs), contributed to eradicate the doubts of inevitable promiscuity that restrained covalent drug discovery programs. As occurs with noncovalent inhibitors, suggested strategies still heavily rely on the optimization of the non-bonding interactions as primary selectivity keys, with an additional focus on tailoring the warhead reactivity to the desired target nucleophilicity.
The mechanism of action of covalent drugs involves the formation of a bond between their electrophilic warhead group and a nucleophilic residue of the protein target. The recent advances in covalent ...drug discovery have accelerated the development of computational tools for the design and characterization of covalent binders. Covalent docking algorithms can predict the binding mode of covalent ligands by modeling the bonds and interactions formed at the reaction site. Their scoring functions can estimate the relative binding affinity of ligands towards the target of interest, thus allowing virtual screening of compound libraries. However, most of the scoring schemes have no specific terms for the bond formation, and therefore it prevents the direct comparison of warheads with different intrinsic reactivity. Herein, we describe a protocol for the binding mode prediction of covalent ligands, a typical virtual screening of compound sets with a single warhead chemistry, and an alternative approach to screen libraries that include various warhead types, as applied in recently validated studies.