scholarly journals Functional group interaction profiles: a general treatment of solvent effects on non-covalent interactions

2020 ◽  
Vol 11 (17) ◽  
pp. 4456-4466 ◽  
Author(s):  
Mark D. Driver ◽  
Mark J. Williamson ◽  
Joanne L. Cook ◽  
Christopher A. Hunter
Keyword(s):  
Free Energy ◽  
Solvent Effects ◽  
Functional Group ◽  
Group Interaction ◽  
General Treatment ◽  
Effect Of Solvent ◽  
Non Covalent Interactions ◽  
Covalent Interactions ◽  
Quantitative Tool

Functional group interaction profiles are a quantitative tool for predicting the effect of solvent on the free energy changes associated with non-covalent interactions.

scholarly journals Calculating the Full Free Energy Profile for Covalent Modification of a Druggable Cysteine in Bruton’s Tyrosine Kinase

2020 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Christopher Rowley
Keyword(s):  
Free Energy ◽  
Gibbs Energy ◽  
Tyrosine Kinase ◽  
Binding Affinity ◽  
Covalent Modification ◽  
Energy Profile ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Linkage ◽  
Non Covalent Interactions ◽  
Covalent Interactions

<p>Targeted Covalent Inhibitors bind to their targets both covalent and non-covalent modes, providing exceptionally high affinity and selectivity. These inhibitors have been effectively employed as inhibitors of protein kinases, with Taunton and coworkers (<i>Nat. Chem. Biol.</i> <b>2015</b>, 11 (7), 525–531) reporting a notable example of a TCI with a cyanoacrylamide warhead that forms a covalent thioether linkage to an active-site cysteine (Cys481) of Bruton's tyrosine kinase. The specific mechanism of the binding and the relative importance of the covalent and non-covalent interactions is difficult to determine experimentally, but established simulation methods for calculating the absolute binding affinity of an inhibitor cannot describe the covalent bond forming steps. Here, an integrated approach using alchemical free energy perturbation</p><p>and QM/MM molecular dynamics methods was employed to model the complete Gibbs energy profile for the covalent inhibition of BTK by a cyanoacrylamide TCI. These calculations provide a rigorous and complete absolute Gibbs energy profile of the covalent modification binding process. The mechanism is ionic, where the target cysteine is deprotonated to form a nucleophilic thiolate, which then undergoes a facile conjugate addition to the electrophilic functional group to form a bond with the non covalently bound ligand. This model predicts that the formation of the covalent linkage makes binding 19.3 kcal/mol more exergonic than the non-covalent binding alone. Nevertheless, non-covalent interactions between the ligand and individual amino acid residues in the binding pocket of the enzyme are also essential for ligand binding,</p><p>particularly, van der Waals dispersion forces that have a larger contribution to the binding energy than the covalent component in absolute terms. This model also shows that the mechanism of covalent modification of a protein occurs through a complex series of steps and that entropy, conformational flexibility, non-covalent interactions, and the formation of covalent linkage are all significant factors in the ultimate</p><p>binding affinity of a covalent drug to its target.</p>

Synthesis of unsymmetrical porphyrin triad containing three different porphyrin subunits assembled by covalent and non-covalent interactions

2008 ◽  
Vol 12 (09) ◽  
pp. 1030-1040 ◽  
Author(s):  
Sokkalingam Punidha ◽  
Smita Rai ◽  
Mangalampalli Ravikanth
Keyword(s):  
Building Block ◽  
Functional Group ◽  
Photophysical Properties ◽  
Time Resolved Fluorescence ◽  
Efficient Energy Transfer ◽  
Time Resolved ◽  
Fluorescence Studies ◽  
Efficient Energy ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Cis-21,23-dithiaporphyrin building block containing one iodophenyl and one pyridyl functional group at meso positions was synthesized by condensing unsymmetrical thiophene diol and symmetrical 16-thiatripyrrin under refluxing propionic acid conditions. The 21,23-dithiaporphyrin building block was coupled with mono-functionalized 21-thiaporphyrin building block containing meso-phenylethyne functional group under mild Pd (0) coupling conditions. The steady-state and time-resolved fluorescence studies support an efficient energy transfer in the singlet excited state from N 3 S porphyrin subunit to N 2 S 2 porphyrin subunit in the dyad. The N 3 S - N 2 S 2 porphyrin dyad was then treated with RuTPP ( CO )( EtOH ) in toluene at refluxing temperature and purified by column chromatography to afford a porphyrin triad containing N 3 S , N 2 S 2 and RuN 4 porphyrin subunits assembled using both covalent and non-covalent interactions. The photophysical properties showed the fluorescence quenching of N 3 S and N 2 S 2 porphyrin subunits in triad due to heavy ruthenium ion which was coordinated to meso-pyridyl ' N ' of N 2 S 2 porphyrin subunit of porphyrin triad.

scholarly journals Symmetry-Adapted Perturbation Theory Decomposition of the Reaction Force: Insights into Substituent Effects Involved in Hemiacetal Formation Mechanisms

2019 ◽  
Author(s):  
Wallace Derricotte
Keyword(s):  
Perturbation Theory ◽  
Functional Group ◽  
Reaction Force ◽  
Substituent Effects ◽  
Formation Mechanisms ◽  
Lower Activation ◽  
Non Covalent Interactions ◽  
Force Components ◽  
Covalent Interactions ◽  
Lower Activation Energy

<div>The decomposition of the reaction force based on symmetry-adapted perturbation theory (SAPT) has been proposed. This approach was used to investigate the subtituent effects along the reaction coordinate pathway for the hemiacetal formation mechanism between methanol and substituted aldehydes of the form CX<sub>3</sub>CHO (X = H, F, Cl, and Br), providing a quantitative evaluation of the reaction-driving and reaction-retarding force components. Our results highlight the importance of more favorable electrostatic and induction effects in the reactions involving halogenated aldehydes that leads to lower activation energy barriers. These substituent effects are further elucidated by applying the functional-group partition of symmetry-adapted</div><div>perturbation theory (F-SAPT). The results show that the reaction is largely driven by favorable direct non-covalent interactions between the CX<sub>3</sub> group on the aldehyde and the OH group on methanol.</div>

scholarly journals Crystal structures ofp-substituted derivatives of 2,6-dimethylbromobenzene with ½ ≤Z′ ≤ 4

2016 ◽  
Vol 72 (12) ◽  
pp. 1762-1767
Author(s):  
Angélica Navarrete Guitérrez ◽  
Gerardo Aguirre Hernández ◽  
Sylvain Bernès
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonding ◽  
Crystal Structures ◽  
Functional Group ◽  
Molecular Symmetry ◽  
Asymmetric Unit ◽  
Structure Feature ◽  
Non Covalent Interactions ◽  
Derivatives Of ◽  
Covalent Interactions

The crystal structures of four bromoarenes based on 2,6-dimethylbromobenzene are reported, which are differentiated according the functional groupXplacedparato the Br atom:X= CN (4-bromo-3,5-dimethylbenzonitrile, C9H8BrN), (1),X= NO2(2-bromo-1,3-dimethyl-5-nitrobenzene, C8H8BrNO2), (2),X= NH2(4-bromo-3,5-dimethylaniline, C8H10BrN), (3) andX= OH (4-bromo-3,5-dimethylphenol, C8H9BrO), (4). The content of the asymmetric unit is different in each crystal,Z′ = ½ (X= CN),Z′ = 1 (X= NO2),Z′ = 2 (X= NH2), andZ′ = 4 (X= OH), and is related to the molecular symmetry and the propensity ofXto be involved in hydrogen bonding. In none of the studied compounds does the crystal structure feature other non-covalent interactions, such as π–π, C—H...π or C—Br...Br contacts.

scholarly journals Calculating the Full Free Energy Profile for Covalent Modification of a Druggable Cysteine in Bruton’s Tyrosine Kinase

2020 ◽  
Author(s):  
Ernest Awoonor-Williams ◽  
Christopher Rowley
Keyword(s):  
Free Energy ◽  
Gibbs Energy ◽  
Tyrosine Kinase ◽  
Binding Affinity ◽  
Covalent Modification ◽  
Energy Profile ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Linkage ◽  
Non Covalent Interactions ◽  
Covalent Interactions

<p>Targeted Covalent Inhibitors bind to their targets both covalent and non-covalent modes, providing exceptionally high affinity and selectivity. These inhibitors have been effectively employed as inhibitors of protein kinases, with Taunton and coworkers (<i>Nat. Chem. Biol.</i> <b>2015</b>, 11 (7), 525–531) reporting a notable example of a TCI with a cyanoacrylamide warhead that forms a covalent thioether linkage to an active-site cysteine (Cys481) of Bruton's tyrosine kinase. The specific mechanism of the binding and the relative importance of the covalent and non-covalent interactions is difficult to determine experimentally, but established simulation methods for calculating the absolute binding affinity of an inhibitor cannot describe the covalent bond forming steps. Here, an integrated approach using alchemical free energy perturbation</p><p>and QM/MM molecular dynamics methods was employed to model the complete Gibbs energy profile for the covalent inhibition of BTK by a cyanoacrylamide TCI. These calculations provide a rigorous and complete absolute Gibbs energy profile of the covalent modification binding process. The mechanism is ionic, where the target cysteine is deprotonated to form a nucleophilic thiolate, which then undergoes a facile conjugate addition to the electrophilic functional group to form a bond with the non covalently bound ligand. This model predicts that the formation of the covalent linkage makes binding 19.3 kcal/mol more exergonic than the non-covalent binding alone. Nevertheless, non-covalent interactions between the ligand and individual amino acid residues in the binding pocket of the enzyme are also essential for ligand binding,</p><p>particularly, van der Waals dispersion forces that have a larger contribution to the binding energy than the covalent component in absolute terms. This model also shows that the mechanism of covalent modification of a protein occurs through a complex series of steps and that entropy, conformational flexibility, non-covalent interactions, and the formation of covalent linkage are all significant factors in the ultimate</p><p>binding affinity of a covalent drug to its target.</p>

Dual Electrocatalysis Enables Enantioselective Hydrocyanation of Conjugated Alkenes

2019 ◽  
Author(s):  
Lu Song ◽  
Niankai Fu ◽  
Brian G. Ernst ◽  
Wai-Hang Lee ◽  
Michael O. Frederick ◽  
...  
Keyword(s):  
Computational Analysis ◽  
Functional Group ◽  
Unique Feature ◽  
Chemical Space ◽  
Bond Formation ◽  
Hydrogen Atom Transfer ◽  
Chiral Catalyst ◽  
Potential Control ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using an electrocatalytic strategy. Electrochemistry allows for the seamless combination of two classic radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidant. We harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis sheds light on the origin of enantioinduction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions that direct the enantio-determining C–CN bond formation. This discovery demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.

scholarly journals Syntheses and crystal structures of the anhydride 4-oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione and the related imide 4-(4-bromophenyl)-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione

2020 ◽  
Vol 76 (8) ◽  
pp. 1311-1315
Author(s):  
Andrew Hulsman ◽  
Isabel Lorenzana ◽  
Theodore Schultz ◽  
Breezy Squires ◽  
Brock A. Stenfors ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Functional Group ◽  
Lone Pair ◽  
Ring System ◽  
Private Communication ◽  
Bond Lengths ◽  
Imide Ring ◽  
Non Covalent Interactions ◽  
Covalent Interactions

The syntheses and crystal structures of the two title compounds, C11H10O3 (I) and C17H14BrNO2 (II), both containing the bicyclo[2.2.2]octene ring system, are reported here [the structure of I has been reported previously: White & Goh (2014). Private Communication (refcode HOKRIK). CCDC, Cambridge, England]. The bond lengths and angles of the bicyclo[2.2.2]octene ring system are similar for both structures. The imide functional group of II features carbonyl C=O bond lengths of 1.209 (2) and 1.210 (2) Å, with C—N bond lengths of 1.393 (2) and 1.397 (2) Å. The five-membered imide ring is nearly planar, and it is positioned exo relative to the alkene bridgehead carbon atoms of the bicyclo[2.2.2]octene ring system. Non-covalent interactions present in the crystal structure of II include a number of C—H...O interactions. The extended structure of II also features C—H...O hydrogen bonds as well as C—H...π and lone pair–π interactions, which combine together to create supramolecular sheets.

Dual Electrocatalysis Enables Enantioselective Hydrocyanation of Conjugated Alkenes

2019 ◽  
Author(s):  
Lu Song ◽  
Niankai Fu ◽  
Brian G. Ernst ◽  
Wai-Hang Lee ◽  
Michael O. Frederick ◽  
...  
Keyword(s):  
Computational Analysis ◽  
Functional Group ◽  
Unique Feature ◽  
Chemical Space ◽  
Bond Formation ◽  
Hydrogen Atom Transfer ◽  
Chiral Catalyst ◽  
Potential Control ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using an electrocatalytic strategy. Electrochemistry allows for the seamless combination of two classic radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidant. We harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis sheds light on the origin of enantioinduction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions that direct the enantio-determining C–CN bond formation. This discovery demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.

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