Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding

Sandner, A.; Hüfner-Wulsdorf, Tobias; Heine, A.; Steinmetzer, Torsten; Klebe, G.

doi:10.1021/acs.jmedchem.9b01196

Cited by 18 publications

(23 citation statements)

References 74 publications

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“…Diminishing the solvent exposure of this salt bridge potentially has an influence on its stability. For instance, it has been earlier demonstrated that shielding a salt bridge between ligand and protein from the solvent contributes to the binding 46 . This stabilized salt bridge interaction between Glu71 and Lys53 contributes to the enhanced conformational stability of the αC-helix.…”

Section: Discussionmentioning

confidence: 99%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

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Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.

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Section: Discussionmentioning

confidence: 99%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

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“…In probing the structure activity relationship (SAR) of adenosine derivatives as A 3 AR agonists, we discovered that introduction of a (N)-methanocarba (bicyclo[3.1.0]hexyl) ring system in place of ribose leads to favorable affinity and selectivity. , This rigid ribose substitution pre-establishes a ligand conformation that is highly compatible with the A 3 AR binding requirements, possibly due to entropic reasons. , As demonstrated in both the ribose and methanocarba series, other modifications that are conducive to high A 3 AR affinity are 5′-alkylamide and C2-ethynyl groups, as in 3 – 5 . − A 5′-methyl- or 5′-ethyl-amide group also tends to increase A 3 AR agonist efficacy in functional assays. A C2-(5-chlorothien-2-ylethynyl) substitution was associated with a long duration and efficacy in chronic pain tests.…”

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confidence: 99%

“…12,13 This rigid ribose substitution pre-establishes a ligand conformation that is highly compatible with the A 3 AR binding requirements, possibly due to entropic reasons. 16,17 As demonstrated in both the ribose and methanocarba series, other modifications that are conducive to high A 3 AR affinity are 5′-alkylamide and C2-ethynyl groups, as in 3−5. 18−21 A 5′methyl-or 5′-ethyl-amide group also tends to increase A 3 AR agonist efficacy in functional assays.…”

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confidence: 99%

Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives as A₃ Receptor Agonists

Tosh

Salmaso

Rao

et al. 2020

ACS Med. Chem. Lett.

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A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as A 3 AR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse A 3 AR. The mean affinity enhancement for 5 pairs of 5′methylamides was 11-fold at hA 3 AR and 42-fold at mA 3 AR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hA 3 ARselective 16 (MRS7334) displaying K i 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of 16 and its corresponding riboside 8 suggested a qualitative entropic advantage of 16 in hA 3 AR binding. The 5-F substitution tended to increase hA 3 AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist 4 was shown to interact potently exclusively with A 3 AR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for A 3 AR agonists, which have translational potential for chronic disease treatment.

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“…1. Introduction, [1][2][3][4][5][6][7][8][9][10][11] 2. Review and Perspective Articles, [12][13][14][15][16][17][18][19] 3. Methods Papers, [20][21][22][23][24][25][26][27][28][29] 4.…”

Section: Introductionunclassified

Applications of isothermal titration calorimetry in pure and applied research from 2016 to 2020

Falconer

Schuur

Mittermaier

2021

J of Molecular Recognition

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The last 5 years have seen a series of advances in the application of isothermal titration microcalorimetry (ITC) and interpretation of ITC data. ITC has played an invaluable role in understanding multiprotein complex formation including proteolysistargeting chimeras (PROTACS), and mitochondrial autophagy receptor Nix interaction with LC3 and GABARAP. It has also helped elucidate complex allosteric communication in protein complexes like trp RNA-binding attenuation protein (TRAP) complex.Advances in kinetics analysis have enabled the calculation of kinetic rate constants from pre-existing ITC data sets. Diverse strategies have also been developed to study enzyme kinetics and enzyme-inhibitor interactions. ITC has also been applied to study small molecule solvent and solute interactions involved in extraction, separation, and purification applications including liquid-liquid separation and extractive distillation. Diverse applications of ITC have been developed from the analysis of protein instability at different temperatures, determination of enzyme kinetics in suspensions of living cells to the adsorption of uremic toxins from aqueous streams.

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Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding

Cited by 18 publications

References 74 publications

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives as A₃ Receptor Agonists

Applications of isothermal titration calorimetry in pure and applied research from 2016 to 2020

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Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding

Cited by 18 publications

References 74 publications

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives as A3 Receptor Agonists

Applications of isothermal titration calorimetry in pure and applied research from 2016 to 2020

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Product

Resources

About

Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives as A₃ Receptor Agonists