Automated computational screening of the thiol reactivity of substituted alkenes

Smith, Jennifer; Rowley, Christopher N.

doi:10.1007/s10822-015-9857-0

Cited by 29 publications

(44 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…QM/MM studies have examined the inhibition of cysteine proteases by epoxides [93], aziridines [94], peptidyl aldehydes [95], vinyl sulfones [96], and nitroalkene-based inhibitors [97] of cysteine proteases, among others. It should be noted that some of these studies used DFT methods (e.g., B3LYP) that underestimate the stability of the enolate intermediate [77]. The maturation of these methods will allow computer modeling to contribute to the development of covalent-modifier drugs to the same degree that they have contributed to the development of non-covalent drugs.…”

Section: Qm/mm Models Of Covalent Modificationmentioning

confidence: 99%

“…The calculated stability of the carbanion intermediate vs. the stability of the thioether product for the full data set of model thiol additions from Smith and Rowley[77]. The region of potential TCI warheads is highlighted, where the thiol undergoes a weakly exergonic addition (∆G thioether < 0) through a moderately-stable carbanion intermediate(130 kJ/mol < ∆G intermediate < 180 kJ/mol).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Modeling covalent-modifier drugs

Awoonor-Williams

Walsh

Rowley

2017

Preprint

Self Cite

View full text Add to dashboard Cite

In this review, we present a summary of how computer modeling has been used in the development of covalent modifier drugs. Covalent modifier drugs bind by forming a chemical bond with their target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed. In some cases, this results in irreversible inhibition of the target, but some targeted covalent inhibitor (TCI) drugs bind covalently but reversibly. Computer modeling is widely used in drug discovery, but different computational methods must be used to model covalent modifiers because of the chemical bonds formed. Structural and bioinformatic analysis has identified sites of modification that could yield selectivity for a chosen target. Docking methods, which are used to rank binding poses of large sets of inhibitors, have been augmented to support the formation of protein-ligand bonds and are now capable of predicting the binding pose of covalent modifiers accurately. The pK a 's of amino acids can be calculated in order to assess their reactivity towards electrophiles. QM/MM methods have been used to model the reaction mechanisms of covalent modification. The continued development of these tools will allow computation to aid in the development of new covalent modifier drugs.

show abstract

Section: Qm/mm Models Of Covalent Modificationmentioning

confidence: 99%

mentioning

confidence: 99%

Modeling covalent-modifier drugs

Awoonor-Williams

Walsh

Rowley

2017

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is illustrated in Scheme 1, where the cysteine thiol is deprotonated to form a thiolate before it reacts with an acrylamide functional group of the inhibitor. 17 Due to the deprotonation step, the rate of covalent modification is dependent on the pKa of the cysteine residue; more reactive cysteines tend to have lower pKa's due to the increased probability of the cysteine being in the thiolate state. Scheme 1.…”

mentioning

confidence: 99%

How Reactive are Druggable Cysteines in Protein Kinases?

Awoonor-Williams

Rowley

2018

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Targeted covalent inhibitors (TCIs) have been successfully developed as high-affinity and selective inhibitors of enzymes of the protein kinase family. These drugs typically act by undergoing an electrophilic addition with an active-site cysteine residue, so design of a TCI begins with the identification of a "druggable" cysteine. These electrophilic additions generally require deprotonation of the thiol to form a reactive anionic thiolate, so the acidity of the residue is a critical factor. Few experimental measurements of the p K's of druggable cysteines have been reported, so computational prediction could prove to be very important in selecting reactive cysteine targets. Here we report the computed p K's of druggable cysteines in selected protein kinases that are of clinical relevance for targeted therapies. The p K's of the cysteines were calculated using advanced computational methods based on all-atom replica-exchange thermodynamic integration molecular dynamics simulations in explicit solvent. We found that the acidities of druggable cysteines within protein kinases are diverse and elevated, indicating enormous differences in their reactivity. Constant-pH molecular dynamics simulations were also performed on selected protein kinases, and the results confirmed this varied range in the acidities of druggable cysteines. Many of these active-site cysteines have low exposure to solvent molecules, elevating their p K values. Electrostatic interactions with nearby anionic residues also elevate the p K's of cysteine residues in the active site. The results suggest that some cysteine residues within kinase binding sites will be slow to react with a TCI because of their low acidity. Several oncogenic kinase mutations were also modeled and found to have p K's similar to that of the wild-type kinase.

show abstract

“…Future incorporation of warhead reactivity or covalent reversible warheads may further reduce false positive hits from docking. 11,27 Although the hit rates were not as high as previous covalent docking campaigns 11 , the success rate was still comparable to typical non-covalent virtual screening hit rates.…”

Section: Discussionmentioning

confidence: 67%

“…27 Overly reactive electrophiles may have promiscuous off-target effects, while non-reactive electrophiles may not be able to form a covalent bond with the target. Unsubstituted acrylamides are found in clinically approved agents and are considered mild electrophiles that react with nucleophilic cysteines when receptor and ligand geometry is optimized.…”

Section: Resultsmentioning

confidence: 99%

Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange

Nnadi

Jenkins

Gentile

et al. 2018

J. Chem. Inf. Model.

View full text Add to dashboard Cite

The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening against the highly dynamic target K-RasG12C. While the overall hit rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C. Hydrogen-deuterium exchange mass spectrometry was used to probe the protein dynamics of compound binding to the switch-II pocket and subsequent destabilization of the nucleotide-binding region. SOS-mediated nucleotide exchange assays showed that, contrary to prior switch-II pocket inhibitors, these compounds appear to accelerate nucleotide exchange. This study highlights the efficiency of covalent docking as a tool for the discovery of chemically novel hits against challenging targets.

show abstract

Automated computational screening of the thiol reactivity of substituted alkenes

Cited by 29 publications

References 45 publications

Modeling covalent-modifier drugs

Modeling covalent-modifier drugs

How Reactive are Druggable Cysteines in Protein Kinases?

Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange

Contact Info

Product

Resources

About