Redox Potentials with COSMO-RS: Systematic Benchmarking with Different Databases

Lukáš, Tomaník,; Rulı́s̆ek, Lubomı́r; Slavı́ček, Petr

doi:10.1021/acs.jctc.2c00919

Cited by 9 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, in addition/dissociation of species (H 2 O or CHF 2 COO – ), we employed the 1.9 Δ n kcal·mol –1 “standard state” conversion, where Δ n is the molar change in the process. It must be re-emphasized that all of the above computational approaches have been tested and verified against experimental data in our previous studies. ,,− …”

Section: Methodsmentioning

confidence: 99%

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Motlová,

Šnajdr,

Kutil

et al. 2023

ACS Chem. Biol.

Self Cite

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors used in the clinic typically contain a hydroxamate zinc-binding group (ZBG). However, more recent work has shown that the use of alternative ZBGs, and, in particular, the heterocyclic oxadiazoles, can confer higher isoenzyme selectivity and more favorable ADMET profiles. Herein, we report on the synthesis and biochemical, crystallographic, and computational characterization of a series of oxadiazole-based inhibitors selectively targeting the HDAC6 isoform. Surprisingly, but in line with a very recent finding reported in the literature, a crystal structure of the HDAC6/inhibitor complex revealed that hydrolysis of the oxadiazole ring transforms the parent oxadiazole into an acylhydrazide through a sequence of two hydrolytic steps. An identical cleavage pattern was also observed both in vitro using the purified HDAC6 enzyme as well as in cellular systems. By employing advanced quantum and molecular mechanics (QM/MM) and QM calculations, we elucidated the mechanistic details of the two hydrolytic steps to obtain a comprehensive mechanistic view of the double hydrolysis of the oxadiazole ring. This was achieved by fully characterizing the reaction coordinate, including identification of the structures of all intermediates and transition states, together with calculations of their respective activation (free) energies. In addition, we ruled out several (intuitively) competing pathways. The computed data (ΔG ‡ ≈ 21 kcal·mol–1 for the rate-determining step of the overall dual hydrolysis) are in very good agreement with the experimentally determined rate constants, which a posteriori supports the proposed reaction mechanism. We also clearly (and quantitatively) explain the role of the −CF3 or −CHF2 substituent on the oxadiazole ring, which is a prerequisite for hydrolysis to occur. Overall, our data provide compelling evidence that the oxadiazole warheads can be efficiently transformed within the active sites of target metallohydrolases to afford reaction products possessing distinct selectivity and inhibition profiles.

show abstract

Section: Methodsmentioning

confidence: 99%

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Motlová,

Šnajdr,

Kutil

et al. 2023

ACS Chem. Biol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This process is straightforward and has been explored by others for different sets of molecules . It has been concluded that highly sophisticated quantum chemistry methods offer no advantages as the accuracy of the potentials is limited to around 0.3 V (MAE) when implicit solvation approximation is employed . We expect this performance from the best performing functionals here as well, so we only provide a brief analysis of functional performance and will focus more on the solvation effects present in our molecule set.…”

Section: Resultsmentioning

confidence: 99%

“…As we have seen, the best performing functionals indeed approach the accuracy limit set by the implicit solvent model . Therefore, to further improve the results, we need to understand better the solvation effects present in our benchmark set of PCs.…”

Section: Resultsmentioning

confidence: 99%

Prediction of Redox Power for Photocatalysts: Synergistic Combination of DFT and Machine Learning

Fehér

Madarász

Stirling

2023

J. Chem. Theory Comput.

View full text Add to dashboard Cite

The accurate prediction of excited state properties is a key element of rational photocatalyst design. This involves the prediction of ground and excited state redox potentials, for which an accurate description of electronic structures is needed. Even with highly sophisticated computational approaches, however, a number of difficulties arise from the complexity of excited state redox potentials, as they require the calculation of the corresponding ground state redox potentials and the estimation of the 0–0 transition energies (E 0,0). In this study, we have systematically evaluated the performance of DFT methods for these quantities on a set of 37 organic photocatalysts representing 9 different chromophore scaffolds. We have found that the ground state redox potentials can be predicted with reasonable accuracy that can be further improved by rationally minimizing the systematic underestimations. The challenging part is to obtain E 0,0, as calculating it directly is highly demanding and its accuracy depends strongly on the DFT functional employed. We have found that approximating E 0,0 with appropriately scaled vertical absorption energies offers the best compromise between accuracy and computational effort. An even more accurate and cost-effective approach, however, is to predict E 0,0 with machine learning and avoid the use of DFT for excited state calculations. Indeed, the best excited state redox potential predictions are achieved with the combination of M062X for ground state redox potentials and machine learning (ML) for E 0,0. With this protocol, the excited state redox potential windows of the photocatalyst frameworks could be adequately predicted. This shows the potential of combining DFT with ML in the computational design of photocatalysts with preferred photochemical properties.

show abstract

“…In addition to the cluster-continuum approach, we also employed the conductor-like screening model for real solvents (COSMO-RS) to evaluate the hydration free energies of the Cl – , BF 4 – , and BH 4 – anions. − This is a pragmatic solvent model capable of providing accurate results in a wide range of cases . First, we calculated the gas-phase and aqueous-phase properties of all three ions.…”

Section: Methodsmentioning

confidence: 99%

Unveiling the Borohydride Ion through Force-Field Development

Mamatkulov,

Polák,

Razzokov

et al. 2024

J. Chem. Theory Comput.

Self Cite

View full text Add to dashboard Cite

The borohydride ion, BH 4 − , is an essential reducing agent in many technological processes, yet its full understanding has been elusive, because of at least two significant challenges. One challenge arises from its marginal stability in aqueous solutions outside of basic pH conditions, which considerably limits the experimental thermodynamic data. The other challenge comes from its unique and atypical hydration shell, stemming from the negative excess charge on its hydrogen atoms, which complicates the accurate modeling in classical atomistic simulations. In this study, we combine experimental and computer simulation techniques to devise a classical force field for NaBH 4 and deepen our understanding of its characteristics. We report the first measurement of the ion's activity coefficient and extrapolate it to neutral pH conditions. Given the difficulties in directly measuring its solvation free energies, owing to its instability, we resort to quantum chemistry calculations. This combined strategy allows us to derive a set of nonpolarizable force-field parameters for the borohydride ion for classical molecular dynamics simulations. The derived force field simultaneously captures the solvation free energy, the hydration structure, as well as the activity coefficient of NaBH 4 salt across a broad concentration range. The obtained insights into the hydration shell of the BH 4 − ion are crucial for accurately modeling and understanding its interactions with other molecules, ions, materials, and interfaces.

show abstract

Redox Potentials with COSMO-RS: Systematic Benchmarking with Different Databases

Cited by 9 publications

References 50 publications

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Prediction of Redox Power for Photocatalysts: Synergistic Combination of DFT and Machine Learning

Unveiling the Borohydride Ion through Force-Field Development

Contact Info

Product

Resources

About