Implicit and Explicit Solvent Effects on the Global Reactivity and the Density Topological Parameters of the Preferred Conformers of Caespitate

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This article explores the effect of implicit and explicit solvent on the global reactivity and density topological parameters of the preferred conformers of caespitate, a molecule with potential biological activity. The caespitate molecule was subjected to conformational search and DFT calculations to obtain stable structures. The implicit solvent model was used to simulate water, chloroform, acetonitrile, and DMSO solvents, while the explicit solvent was simulated using the ONIOM QM1/QM2 model. The global reactivity indexes were evaluated using the conceptual-DFT approach. The findings suggest that the solvent environment significantly affects the global reactivity of caespitate. The findings are well-presented and offer valuable insights into the molecule's behavior. One suggestion for the author could be to provide a brief summary at the beginning of the article to help readers grasp the main points before delving into the technical details.

Author Response

Response to the reviewers

We thank to the reviewers for their revisions, efforts and comments that we found very helpful in improving this work.

The additional information and the changes are highlighted in yellow in the revised version of the manuscript. The answers to each comment are listed below.

Reviewer 1

Comment 1

This article explores the effect of implicit and explicit solvent on the global reactivity and density topological parameters of the preferred conformers of caespitate, a molecule with potential biological activity. The caespitate molecule was subjected to conformational search and DFT calculations to obtain stable structures. The implicit solvent model was used to simulate water, chloroform, acetonitrile, and DMSO solvents, while the explicit solvent was simulated using the conceptual-DFT approach. The findings suggest that the solvent environment significantly affects the global reactivity of caespitate. The findings are well-presented and offer valuable insights into the molecule´s behavior. One suggestion for the author could be to provide a brief summary at the beginning of the article to help readers grasp the main points before delving into the technical details.

Answer to Comment 1

A brief summary was included on page 2 at the beginning of the Introduction section incorporating the main points of the manuscript in a general way before delving into the technical details:

Acylphloroglucinols (ACPLs) are phytochemical compounds with pharmacological properties. One relevant chemical characteristic of ACPLs is the formation of intramolecular non-covalent interactions in their structures, such as intramolecular hydrogen bonds (IHBs). These IHBs could be responsible of the chemical reactivity and the biological activity observed in these compounds. On the other hand, it is important simulate the solvent effect on the molecules. The effect of the solvent can be modeled with implicit models, which assume the solute put into a cavity within a continuous dielectric medium simulating the solvent. Some more used implicit models are Polarizable Continuum Model (PCM), or Universal Solvation Model based on Density (SMD). Also, molecules of solvent can be incorporated explicitly to the system surrounding to the solute to model the solute-solvent interactions. One explicit model widely used is the Our own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM), which uses different levels of theory to calculate different parts of the system, generally the solute is treated with high level of theory calculation while the molecules of solvent are treated at lower level of theory. The chemical reactivity of ACPLs can be studied by global reactivity parameters based on conceptual Density Functional Theory (c-DFT) approach. c-DFT is based on describing chemical concepts from quantitative prediction of the Koopmans theorem and the Kohn-Sham formalism, i.e., the energy of HOMO related to vertical ionization potential (IP), and the energy of LUMO related to vertical electron affinity (EA). The Quantum Theory of Atoms In Molecules (QTAIM) is used to characterize the intramolecular hydrogen bonds (IHBs) through of parameters obtained from the electron density. As part of the validation of the theoretical methodology used, experimental spectroscopic data are very useful to compare the calculated values obtained, for example experimental ¹H and ¹³C NMR spectra of ACPLs have been reported, and our calculations of ¹H and ¹³C NMR spectra are in agreement with them in both implicit and explicit calculated systems.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The caespitate molecule extracted from the Helichrysum caespititium plant (the Asteraceae family) is a real and perspective pharmacological agent against tuberculosis. Therefore, the study of properties of this molecule is important. The presented manuscript of Liliana Mammino et al. provides  extensive quantum chemical information on the properties of Z-caespitate conformers in a number of popular solvents. The work may be published in Computation after taking into account a minor comments.

1. How did the authors determine that 31 molecules are sufficient for the explicite solvent model. Is there a convergence of computational results as the number of surrounding molecules increases.

2. What is a reason to choose 2 kcal/mol as a boundary to cut off the number of conformers? May be 1.0 or 1.5 kcal/mol was enough?

3. What can the reaction indices obtained in the paper say about the real reactivity of conformers? Is it possible to conclude something about the correlation of antimicrobial activity of the studied molecule based on reactivity indices (e.g. on the electrophilicity index)?  And in general, can the authors draw a practical conclusion about the nature of the reactivity of Z-caespitate. Is it related to the number of Internal Hydrogen Bonds (IHB) ?

Author Response

Response to the reviewers

We thank to the reviewers for their revisions, efforts and comments that we found very helpful in improving this work.

The additional information and the changes are highlighted in yellow in the revised version of the manuscript. The answers to each comment are listed below.

Reviewer 2

The caespitate molecule extracted from the Helichrysum caespititium plant (the Asteraceae family) is a real and perspective pharmacological agent against tuberculosis. Therefore, the study of properties of this molecule is important. The presented manuscript of Liliana Mammino et al. provides extensive quantum chemical information on the properties of Z-caespitate conformers in a number of popular solvents. The work may be published in Computation after taking into account a minor comments.

Comment 1

1. How did the authors determine that 31 molecules are sufficient for the explicit solvent model. Is there a convergence of computational results as the number of surrounding molecules increases.

Answer to Comment 1

We have used 31 molecules of explicit solvent in order to adequately represent the first solvation shell, and then satisfactorily characterize the use of an explicit microsolvation model. There are advantages to use the explicit solvation model. However, it becomes more complicated to determine the structure of the solvation shells with the increase in the number of solvent molecules. We consider that using an average number of 31 molecules of each solvent around the different structures of the caespitate molecules studied and treated simultaneously with the ONIOM method (QM1/QM2) are sufficient to adequately reproduce the experimental data reported as illustrated in the present work.

It should be noted that test calculations were carried out considering a larger number of molecules for a solvent (60 water molecules) and the results obtained were similar for the complex studied.   

Comment 2

2. What is a reason to choose 2 kcal/mol as a boundary to cut off the number of conformers? May be 1.0 or 1.5 kcal/mol was enough?

Answer to Comment 2

Although conformers with relative energy  3.5 kcal/mol are usually viewed as potentially interesting in the investigation of biological activities (i.e., as potentially responsible for the pharmacological activity), see Reference [15], this study considers a high number of conformers, including high energy ones, obtained through three steps: 1) MM method considering relative energies ≤ 6 kcal mol^-1, 2) DFT/APFD/6-31+G(d) level of theory considering relative energies ≤ 4 kcal mol^-1, and finally, 3) DFT/APFD/6-311+G(2d,p) level of theory considering relative energies ≤ 2 kcal mol^-1.

Comment 3

3. What can the reaction indices obtained in the paper say about the real reactivity of conformers? Is it possible to conclude something about the correlation of antimicrobial activity of the studied molecule based on reactivity indices (e.g. on the electrophilicity index)? And in general, can the authors draw a practical conclusion about the nature of the reactivity of Z-caespitate. Is it related to the number of Internal Hydrogen Bonds (IHB)?

Answer to Comment 3

A brief paragraph was included on page 13 at the 3.3. Global reactivity indices section incorporating information reported about the relationship between global reactivity descriptors (specifically electrophilicity index) of antimicrobial compounds with toxicity:

The use of global reactivity descriptors is common in predicting the activity of antimicrobial compounds [41-44]. For example, the electrophilicity index, ω, has been used in the evaluation of the toxicity of molecules with anti-microbial activity, allowing to quantify the drug-receptor biological interaction [45]. A low value of electrophilicity index, ω, is related with low toxicity [43, 44]. In our case, the caespitate conformers, both in implicit and explicit chloroform solvent, C1 and C1E show a lower value of ω, suggesting a lower toxicity respect to the other conformers.

References [41-45] were incorporated:

41. Parthasarathi, R.; Padmanabhan, J.; Sarkar, U.; Maiti, B.; Subramanian, V.; Chattaraj, P.K. Toxicity Analysis of Benzidine Through Chemical Reactivity and Selectivity Profiles: A DFT Approach. Internet Electron. J. Mol. Des. 2003, 2, 798–813, ISSN 1538-6414. Available online: http://www.biochempress.com/av02_0798.html (accessed on 19 December 2023)
42. Pradeep Kumar, C. B.; Raghu, M. S.; Prasad, K.; Chandrasekhar, S.; Budi, J. B.; Alharthi, F.; Prashanth M. K.; K, Y. K. Expatiating biological excellence of 2,3-disubstituted quinazolin-4(1H)-ones against Mycobacterium tuberculosis and DNA using docking, spectroscopic and DFT studies. New J. Chem. 2020, 45, 403-414. https://doi.org/10.1039/D0NJ03800H
43. Mishra, V. R.; Ghanavatkar, C. W.; Mali, S. N.; Chaudhari, H. K.; Sekar, N. Schiff base clubbed benzothiazole: synthesis, potent antimicrobial and MCF-7 anticancer activity, DNA cleavage and computational study. Biomol. Struct. Dyn. 2019, 38:6, 1772-1785. https://doi.org/10.1080/07391102.2019.1621213
44. Mali, S.N.; Pandey, A.; Thorat, B.R; Lai, C. Multiple 3D- and 2D-quantitative structure–activity relationship models (QSAR), theoretical study and molecular modeling to identify structural requirements of imidazopyridine analogues as anti-infective agents against tuberculosis. Struct Chem. 2022, 33, 679–694. https://doi.org/10.1007/s11224-022-01879-2
45. Eno, E.A.; Mbonu, J.I.; Louis, H.; Patrick-Inezi, F.S.; Gber, T.E.; Unimuke, T.O.; Okon, E.E.D.; Benjamin, I.; Offiong, O. E. Antimicrobial activities of 1-phenyl-3-methyl-4-trichloroacetyl-pyrazolone: Experimental, DFT studies, and molecular docking investigation, J. Indian Chem. Soc. 2022, 99, 7, 100524, ISSN 0019-4522, https://doi.org/10.1016/j.jics.2022.100524

The sentence in page 14, at the 3.4. Density topological parameters section, about the formation of IHBs in the Z isomer of caespitate respect to E isomer was corrected as follows:

The interesting ability of the Z isomer of caespitate to form two IHBs has been studied in previous works [9-12, 14, 15, 49], in comparison with its E isomer which forms only one IHB.

Also, the following sentence was added in page 14:

Specifically, it has been showed that the formation of the second IHB dominates the conformational preferences in gas and solvent phases [15]. It could explain the bioactivity associated with the Z isomer.

References were renumbered.

Author Response File: Author Response.pdf