A quantum chemical approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson's disease.

Schizophrenia and Parkinson's disease can be controlled with dopamine antagonists and agonists. In order to improve the understanding of the reaction mechanism of these drugs, in this investigation we present a quantum chemical study of 20 antagonists and 10 agonists. Electron donor acceptor capacity and global hardness are analyzed using Density Functional Theory calculations. Following this theoretical approach, we provide new insights into the intrinsic response of these chemical species. In summary, antagonists generally prove to be better electron acceptors and worse electron donors than dopamine, whereas agonists present an electron donor-acceptor capacity similar to that of dopamine. The chemical hardness is a descriptor that captures the resistance of a chemical compound to change its number of electrons. Within this model, harder molecules are less polarizable and more stable systems. Our results show that the global hardness is similar for dopamine and agonists whilst antagonists present smaller values. Following the Hard and Soft Acid and Bases principle, it is possible to conclude that dopamine and agonists are hard bases while antagonists are soft acids, and this can be related to their activity. From the electronic point of view, we have evolved a new perspective for the classification of agonist and antagonist, which may help to analyze future results of chemical interactions triggered by these drugs.

Introduction

Schizophrenia, a type of psychosis, is associated with diverse symptoms such as avolition, catatonia, diminished emotional expression, anhedonia, disorganized speech, delusions, hallucinations and psychomotor abnormality [1-10]. The main hypothesis that could explain schizophrenia is related to the neurotransmitter dopamine. In the dopaminergic system dopamine is synthesized in dopaminergic nerve terminals from the amino acid tyrosine. Then it is absorbed by a vesicular monoamine transporter where is stored until it is used during neurotransmission, which is regulated by the receptors. The dopamine hypothesis of schizophrenia states that the physiological mechanism evolves from an excess of dopamine activity in certain regions of the brain and little dopamine activity in other regions. Several drugs named antipsychotics have been developed to control the symptoms of schizophrenia, which primarily target this dopaminergic pathway [11-37].

The first antipsychotic to be developed in the modern era was chlorpromazine (Largactil ®), introduced in the 1950’s [28-32]. Since then, dozens of drugs with this capacity have been synthesized and tested. The so-called First-Generation Antipsychotics (FGA) are effective for controlling the symptoms of schizophrenia, but they have detrimental extra-pyramidal side effects that curtail long-term treatments. Atypical antipsychotics or Second-Generation Antipsychotics (SGA) had been used since 1989, when clozapine was introduced to the US market [33-35]. The common characteristic of SGA is that they are not only effective for controlling hallucinations and delusions, but also considerably reduce extra-pyramidal side effects. Concerning the prevention of schizophrenia symptoms, SGA can be distinguished from FGA because the former manifest more than one action mechanism. Pharmacodynamic properties reflect SGA affinity for serotonin and dopamine specific receptors. Experiments show that most of the FGA and SGA are antagonists of dopamine and serotonin. They occupy the receptors but do not activate them.

The Third-Generation of Antipsychotics (TGA) includes aripiprazole and cariprazine. Unlike other antipsychotics, these molecules are not dopamine antagonists but agonists, i.e. they occupy and activate the receptors [17-18]. However, in the presence of high extracellular concentrations of dopamine, these drugs compete with dopamine, while also acting as antagonists with many clinical benefits. In summary, they are named “dopamine stabilizers”, as they are agonists in regions with low dopamine concentrations, whereas in areas with high dopamine concentrations, these drugs act as antagonists. Nonetheless, the main action of these drugs is as agonists.

Parkinson’s disease is also related to an imbalance in the level of dopamine. The dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine) was previously successfully used for the treatment of this disorder; however long-term exposure to this drug accelerates the dopamine neurodegenerative process [38-43]. Dopamine receptor agonists such as pramipexole delay complications associated with exposure to L-DOPA and have been successfully used in therapy for Parkinson’s disease [44, 45].

Drugs related to schizophrenia and Parkinson’s disease bind to different dopamine receptors that belong to the family of G-Protein-Coupled Receptors (GPCR). Previous investigations have modeled dopamine receptors, providing important information about the mechanism of ligand-receptor non-covalent interactions [46-56]. Nevertheless, little is known about the intrinsic reactivity of these drugs. In spite of all reports concerning the function of antagonists and agonists, and also studies that consider the receptors, there are no quantum chemistry investigations that compare these two, or that consider different reactivity parameters. It is now well known that antipsychotics act on the receptor of dopamine to alleviate psychosis. Apparently, all approved antipsychotics present some affinity for these receptors. However, these molecules also bind to other receptors. As there is more than one dopamine GPCR participating, it is important to characterize the drugs independently of the receptors. Light bulbs and sockets provide a good analogy to explain the importance of studying these drugs. Some light bulb characteristics are independent of the sockets (for example, light bulbs can have different voltage). If we consider that GPCR are the sockets and the drugs are the light bulbs, it follows that certain characteristics of the drugs are independent of the receptors.

Following these ideas, the main goal of this work is to characterize 20 antagonists and 10 agonists of dopamine as electron donors or as electron acceptors, by using intrinsic reactivity indexes within the context of Chemical Reactivity Theory in DFT (CRDFT) [57-62]. The binding energies of these antipsychotics with dopamine receptors are already reported [46, 53] but we think it still needs to be explained why some drugs behave as agonists and others as antagonists from the quantum chemistry point of view. The intrinsic properties of these drugs may provide some useful insights. Global hardness (η) of each molecule is also a reactivity index that is also reported as a possible parameter useful for the characterization of agonist and antagonist. The conclusions obtained from these reactivity indexes offer a new perspective for the analysis of these drugs.

Methods

Gaussian09 was used for all electronic calculations [63] Geometry optimizations without symmetry constraints were implemented at M06/6-311+G(2d,p) level of theory [64-68] while applying the continuum solvation model density (SMD) with water, in order to mimic a polar environment [69]. Harmonic analyses were calculated to verify local minima (zero imaginary frequencies). Geometries from PubChem database were employed as initial structures for the geometry optimization. Other conformers of each molecule were also optimized but the optimized ground states are those that come from PubChem [70]. Cartesian coordinates of more stable optimized molecules are included as Supporting Information. We also considered protonated states for those molecules with pKa values lower than 7.

In order to analyze electron-donor acceptor properties, vertical ionization energy (I) and vertical electron affinity (A) were obtained from single point calculations of the corresponding cationic and anionic molecules, using the optimized structure of the neutrals. The same level of theory was used for all computations.

In this investigation we analyze 20 antagonists and 10 agonists of dopamine (see Fig 1). These molecules have been chosen due to the following reasons [11]. The selected First-Generation Antipsychotics represent different families of compounds. Haloperidol, trifluperidol, benperidol, spiperone, pipamperone and droperidol are typical antipsychotic of the butyrophenone family. They exhibit high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. These butyrophenones have different receptor binding profiles and exhibited distinctive clinical efficacy. Haloperidol is one of the first drugs used to treat schizophrenia and it is the most commonly used. Trifluperidol is stronger than haloperidol. Benperidol and spiperone are two of the most potent antipsychotics in this family. Moreover, spiperone is used in treating drug-resistant schizophrenia. Pipamperone present a different pharmacological profile and it can be classified as a first-generation typical antipsychotic. It was considered as a forerunner of atypical antipsychotics. Chlorprothixene and clopenthixol are typical antipsychotics of the thioxanthene group. Raclopride is a selective antagonist of dopamine receptors and it can be radiolabelled and used as a tracer for in vitro imaging. Sulpiride belongs to the benzamide class. Within this group of molecules, we can compare ligands of the same family and also ligands from different families.

Fig 1

Molecular formulas.

Molecules that we analyzed in this investigation are presented. To mimic physiological conditions, protonated species are included for those molecules that have pKa values lower than 7.

The First-Generation Antipsychotics have largely given way to Second-Generation Antipsychotics such as risperidone, clozapine, olanzapine, quetiapine and ziprasidone. Clozapine was the first antipsychotic of the second generation that was synthesized and tested. It has antipsychotic action but no Parkinson-like motor side effects and it is one of the most widely used together with risperidone. Clozapine is the most efficacious antipsychotic drug and it is used only for treatment of resistant schizophrenia due to its severe side effects. Olanzapine has a similar structure and it is also a good antipsychotic but with lower side effects. Risperidone, the second atypical antipsychotic quickly became a first-line treatment for acute and chronic schizophrenia because of its preferential side effect profile. Ziprasidone was also developed based upon clozapine and it is used since 1998. All these antipsychotics are widely used in the treatment of schizophrenia.

Aripiprazole and cariprazine are relatively new antipsychotic drugs and represents the Third-Generation of Antipsychotics. They are dopamine system stabilizers. Finally, the agonists that we investigated were selective developed to be agonists and therefore, they are very well characterized as agonists. These molecules were investigated theoretically with docking studies that allow investigating potential sites of interaction [53].

Results and discussion

Electron transfer process

All molecules have chemical properties that can be described in terms of response functions. These response functions refer to modifications in the electronic states of one molecule due to the presence of other molecules. For chemical interactions that are mainly driven by electron transfer processes, these functions have been proven to qualitatively describe and explain fundamental aspects of chemical reactivity [71-75]. In this model, an electron bath constitutes the chemical environment in which chemical species are immersed.

In this investigation, we analyzed the drugs by studying the global response on the specific section of molecules when they are immersed in an idealized bath that may either donate or accept charge. The main target is to classify the drugs as either electron donors or acceptors. The hypothesis is that those molecules that are agonists to dopamine should have electron transfer properties similar to this neurotransmitter. They will therefore interact to the receptors and activate them (as dopamine does). Molecules that are antagonists of this neurotransmitter must have a different capacity to transfer charge. They should be different electron-donor acceptors of dopamine, which explains why they interact to the receptors but do not activate them.

The response functions that we used in this investigation are the electrodonating (w-) and electroaccepting (w+) powers, previously reported by Gázquez et al [61,62]. These authors defined the propensity to donate charge or ω- as follows: whereas the propensity to accept charge or ω+ is defined as

I and A are vertical ionization energy and vertical electron affinity, respectively. Lower values of ω- imply greater capacity for donating charge. Higher values of ω+ imply greater capacity for accepting charge. In contrast to I and A, ω- and ω+ refer to charge transfers, not necessarily from one electron. This definition is based on a simple charge transfer model expressed in terms of chemical potential and hardness. The Donor-Acceptor Map previously defined [71] is a useful graphic tool that has been used successfully in many different chemical systems [72-75]. We have plotted ω- and ω+ (Fig 2) on this map, enabling us to classify substances as either electron donors or acceptors. Electrons are transferred from good donor systems (down to the left of the map) to good electron acceptor systems (up to the right of the map).

Fig 2

DAM.

Donor-Acceptor Map.

Fig 3 presents the DAM for antipsychotics and drugs for Parkinson’s disease (antagonists and agonists) that have been used for several years. Corresponding molecular structures are included in Fig 1. We should remember that FGAs and SGAs are both antagonists, whereas TGAs are partial agonists. We included other molecules reported as dopamine agonist in the analysis [46,53]. As can be seen in Fig 3, agonists are located close to dopamine in the DAM. This means that they are more like dopamine than antagonists. i.e. they are good electron donors being the best quinpirole. The best electron acceptors (up to the right) are FGAs classified as butyrophenones, an important family of compounds with antipsychotic properties. In the middle of the map we found SGAs and other FGAs. They are not as good electron donors as neurotransmitter and they are also worse electron acceptors than butyrophenones. The TGAs are molecules that are partial agonists and are located close to dopamine in the DAM. It is clear that these agonists or antagonists present different capacity to either donate or accept electrons, and correspondingly, they could show different efficacy for controlling schizophrenia or Parkinson’s disease.

Fig 3

DAM of molecules under study.

Donor-Acceptor Map of antagonists and agonists. Dopamine is included for comparison.

In summary, analysis of the DAM shows that antagonists are better electron acceptors and worse electron donors than dopamine. Within this model, these drugs act as antagonist, as they do not have the same capacity to accept or donate electrons as dopamine. Conversely, they manifest the opposite, which may relate to the fact that they block the receptor without activating it. Instead, the agonists studied here present similar potential for donating electrons, which is possibly an indication of the activation capacity of these drugs.

Our model is based on the intrinsic reactivity indexes that can be obtained from quantum chemistry calculations, allowing us to classify these drugs with precision as either electron donors or electron acceptors. Agonists have similar electron donor capacity as dopamine. Contrastingly, antagonists are better electron acceptors and worse electron donors than dopamine. This model may also explain the partial agonist action of TGA, as the electron donor acceptor capacity of these molecules is similar to that of dopamine (they are close to this molecule in the DAM); it thus represents a better electron donor and worse electron acceptor than other antipsychotics. In summary, within this model we suggest a classification of these drugs based on the charge transfer process.

Chemical hardness (η)

One of the main goals of quantum chemistry is to offer accessible and elegant methods capable to explain complicated chemical processes. Over the last three decades, theoretical chemists have developed concepts and principles in order to understand different reactions and interactions. Pearson introduced one interesting and qualitatively model in the early 1960´s [57-59] as an attempt to unify the concepts of organic chemical reactivity with inorganic chemistry reactions. Pearson’s model is named as the Hard and Soft Acid and Base (HSBA) principle and it is an elegant theory widely used in chemistry to explain stability, reaction mechanisms and also, to describe the sensitivity and performance of explosive materials [76]. In 1983, Pearson and Parr [60] reported a quantitative definition within DFT framework of the chemical hardness (η) that is approximated as follows (I and A are vertical ionization energy and vertical electron affinity, respectively)

Hardness refers to stability and polarizability of the molecules. It captures the resistance of a chemical species to modify the number of electrons [57-60,62]. A Lewis acid is an electron acceptor and a base is an electron donor. In general, HSBA states that soft acids react and form stronger bonds with soft bases, whereas hard acids are mainly bonded to hard bases. In attempt to give more insights to characterize agonists and antagonists, chemical hardness was obtained for all the molecules that we are investigating. Fig 4 reports these results. FGAs (black rhombus) and SGAs (grey rhombus) show lower η than dopamine (the exception is risperidoneH+). TGAs (blue rhombus) and must of the agonists (white rhombus) have similar values of η. According to these results, antagonists are softer and more polarizable molecules than dopamine, whereas most agonists are similar to dopamine, i.e. agonists and dopamine are less polarizable than antagonists that may undergo polarizable.

Fig 4

Global hardness (η).

Global hardness for all the molecules studied in this investigation. FGAs (black rhombus) SGAs (grey rhombus) TGAs (blue rhombus) and agonists (white rhombus).

Analyzing together the electron-donor acceptor capacity from the previous section with the chemical hardness, it is possible to conclude that dopamine and agonists are hard molecules and also good electron donors. Antagonists are soft molecules and good electron acceptors. Following the HSBA principles, dopamine and agonist are hard bases whilst antagonists are soft acids. According to this principle, dopamine and agonists react in a similar way and this could be related to the ability to activate the receptor. On the other hand, antagonists react different since they are soft acids, and this can explain why they block the receptors and fail to activate them. Thus, within this model we suggest that hardness and the electron donor-acceptor properties may be useful to classify these drugs. The classification as hard and soft acids and bases offers a smart methodology, which helps us to categorize agonists and antagonists.

Conclusions

The intrinsic reactivity-index using quantum chemistry calculations provide a precise classification of these drugs as hard/soft acid/bases.

Within the HSBA principles, dopamine and agonist are hard bases while antagonists are soft acids. Dopamine and agonists respond in a similar way and this could be related to the ability to activate the receptor. Antagonists are soft acids and this can explain why they block the receptors and fail to activate them.

We proposed a computational model able to classify agonist and antagonist, based on an analysis of the intrinsic reactivity of the molecules. This provides a new perspective in order to describe antagonists and agonists related with schizophrenia and Parkinson’s disease. We anticipate that this model will help to understand future experimental and theoretical results concerning to these significant systems.

Cartesian coordinates of the optimized structures.

(PDF)

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10 Sep 2019

PONE-D-19-20849

A quantum chemistry approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease

PLOS ONE

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Reviewer #1: I congratulate the authors for the work, however, in the present work the authors using Electron donor acceptor capacity and global hardness are analyzed using Density Functional Theory calculations. Following this theoretical approach, the authors provide new insights into the intrinsic response of these chemical species. Thus, the method presented might mean a new contribution to the different criteria, however, before acceptance for publication I would recommend important changes to be taken into account in the manuscript. After careful evaluation of your article, there are some numbers of comments to be addressed follows:

1. The author should describe the dopaminergic pathway details in the introduction part.

2. In the ligand-receptor interaction the authors, should describe about the ligand-receptor non-covalent interactions. Further, the drug is bonded to the receptor?

3. The electron bath is unclear in the receptors (GPCR proteins). The authors should describe the electron transfer bath and provide the image.

4. The authors claimed, the dopamine electron transfer properties are similar to this neurotransmitter but the authors did not describe about the similarities.

5. The authors should provide the clear image about the “Agonists have similar electron donor capacity and therefore they may also transfer electrons to the receptors and activate them. Contrastingly, antagonists would accept electrons from the receptors, impeding activation”.

Reviewer #2: The authors present their thesis clearly. The article is well written in English. Authors analyses physico-chemistry properties of a set of molecules composed of antipsychotic drugs and agonist drug to the dopamine receptor. Properties such as acceptor of donor of electrons are computed by DFT method. The method and the atomic base-is set (M06/6-311+G(2d,p)) are well established for this kind of calculation.

My concern is about the complexity of receptors and the list of molecules.

The authors said that they are not talking about receptor. Receptors are not receptor-like in fig 4, but are receptors and family of receptors. Each molecule binds on several receptors, which are identified or even sometimes not identified. Analysis of sequences of different receptors reveals that the active site of this GPCR family is kite different. The activity of the molecule if the binding part of the mechanism is well-known this some crystallographic structure, the mechanism of the biologic response is unknown.

In conclusion of this remark, an analysis of site in term of residues should give a validation if site is fill with residues acceptor of electrons, an electron donor molecule should have a good binding.

The list of molecules studied is concise in the article. First, second, and third generations of antipsychotic drugs and agonists are more numerous than in the list of molecules. A full list is necessary to validate the assumption of agonist or antagonist drugs is correlated this the acceptor or donor of electrons. The case is more complicated than a molecule has nitrogen atom or halogen it is antagonism, and a molecule has a hydroxy function; it is an agonist.

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19 Sep 2019

PONE-D-19-20849

A quantum chemistry approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease

Professor Dennis R. Salahub

Academic Editor

PLOS ONE

Dear Prof. Salahub,

We thank the reviewers for their priceless evaluations and their very useful comments. Since both reviewers have raised the issue of bringing in the properties of the receptors, we would like to start explaining why we do not include the properties of the receptors.

In this investigation we provide a classification of thirty antipsychotics in terms of their electron donor-acceptor properties that give information about the intrinsic reactivity of these molecules. These characteristics of the drugs are independent of the receptors, and allow us to have a clear and straightforward classification of the antipsychotics, which, otherwise, would not be possible to achieve. Currently, a way to classify the antipsychotics is based on In Vivo Rotational Experiments with injured rats. In one of these reports, “a lesion on rats was performed on the left side of the medial forebrain bundle in the brain” and the conclusion is that “the rotations produced upon agonist Challenger were clockwise”. These experiments are extremely impressive with conclusions that are based on the behavior of four rats that have been injured. We believe that with our quantum chemical calculations, it is possible to have another classification and both classifications can complement each other.

The study of the receptors is a matter of a different investigation and in fact, there are previous studies that predict the binding sites and report binding energies of these antipsychotics with dopamine receptors (see for example references 46 and 53 of the manuscript). In spite of all the studies concerning the drugs and the receptors reported until now, there are not investigations regarding the intrinsic characteristics of these drugs. We strongly believe that it is still needed to be explained why some drugs behave as agonists and others as antagonists from the quantum chemistry point of view, and the intrinsic characteristics that we report here could give some solid ideas.

The intrinsic characteristics of these drugs allow us to classify them and also give us some ideas about possible reaction mechanisms, but it is clear that, to speak about the reaction mechanisms it is important to consider all the reactants, in this case, drugs and receptors. In this sense, the paper in the original version was confusing since we included a possible reaction mechanism and, as both reviewers established, it is not possible to analyze a reaction mechanism with only one of the reactants. In that case, the study of the GPCR proteins is also necessary. What we can do is a clear classification. For this reason, we removed, from the original version, all the information concerning the reaction mechanism, including Figure 4 and 6. Specifically, the following paragraphs were deleted in this new version:

We assume that the receptors (GPCR proteins) are represented by the electron bath and, in this context; they are able to either donate charge to the drugs or accept charge from them.

It is known that these drugs interact with GPCR through ligand-receptor non-covalent interactions but what happens once the drug is bonded to the receptor? Our premise is that once the drug interacts with the receptor, a charge-transfer process initiates. Dopamine binds to the receptors and activates them, and some of this activation may be the result of electron transfer; if this is the case, dopamine will donate electrons to the receptors.

… and therefore the may also transfer electrons to the receptors and activate them

… would accept electrons form the receptors, impeding activation.

The model presented in here gives prominence to the charge transfer process in the action mechanism: drugs interact with the receptors and a charge transfer occurs. Dopamine activates the receptors by donating electrons to GPCRs. Agonists also transfer electrons to the receptors and activated them, as they have similar electron donor capacity. Conversely, the antagonists accept electrons from the receptors, so activation does not proceed.

Figure 4. Schematic representation of the action mechanisms proposed in this report. Dopamine and agonist are good electron donors (represented by a red hexagon) and therefore, transfer electrons to the receptor. Antagonists (represented as a blue hexagon) are good electron acceptors and may accept electrons from the receptor.

Figure 6. Schematic representation of the action mechanism proposed in this report. Dopamine and agonist are hard molecules and good electron donors (represented by a red hexagon) and therefore they transfer electrons to the receptor without polarization. Antagonists (represented as a blue deformed hexagon) are soft molecules and good electron acceptors; they are polarizable and may accept electrons from the receptor.

Finally, in here we present and explain other modifications that were carried out on the manuscript. We hope to have been able to solve and properly answered the reviewers' concerns.

With my best regards

Prof. Ana Martínez

Reviewer #1:

1. The author should describe the dopaminergic pathway details in the introduction part.

Authors’ reply

Following this suggestion, the first paragraph of the introduction was modified as follows:

Schizophrenia, a type of psychosis, is associated with diverse symptoms such as avolition, catatonia, diminished emotional expression, anhedonia, disorganized speech, delusions, hallucinations and psychomotor abnormality [1-10]. The main hypothesis that could explain schizophrenia is related to the neurotransmitter dopamine. In the dopaminergic system dopamine is synthesized in dopaminergic nerve terminals from the amino acid tyrosine. Then it is absorbed by a vesicular monoamine transporter where is stored until it is used during neurotransmission, which is regulated by the receptors. The dopamine hypothesis of schizophrenia states that the physiological mechanism evolves from an excess of dopamine activity in certain regions of the brain and little dopamine activity in other regions. Several drugs named antipsychotics have been developed to control the symptoms of schizophrenia, which primarily target this dopaminergic pathway [11-37].

Reviewer #1:

2. In the ligand-receptor interaction the authors, should describe about the ligand-receptor non-covalent interactions. Further, the drug is bonded to the receptor?

Authors’ reply

We thank the reviewer for this comment that is very interesting. However, with the results reported here it is not possible to analyze the ligand-receptor interaction since the receptor is not included in this investigation. We are focused on the analysis of the drugs.

Reviewer #1:

3. The electron bath is unclear in the receptors (GPCR proteins). The authors should describe the electron transfer bath and provide the image.

Authors’ reply

As we explain before in this letter, we are not including the GPCR proteins in this study.

Reviewer #1:

4. The authors claimed, the dopamine electron transfer properties are similar to this neurotransmitter but the authors did not describe about the similarities.

Authors’ reply

We apologize for the lack of clarity in the explanation. We added the following paragraph

As can be seen in Figure 2, agonists are located close to dopamine in the DAM. This means that they are more like dopamine than antagonists. i.e. they are good electron donors being the best quinpirole.

Reviewer #1:

5. The authors should provide the clear image about the “Agonists have similar electron donor capacity and therefore they may also transfer electrons to the receptors and activate them. Contrastingly, antagonists would accept electrons from the receptors, impeding activation”.

Authors’ reply

As we pointed out before, in this new version we removed all the information concerning the reaction mechanism.

Reviewer #2:

The authors said that they are not talking about receptor. Receptors are not receptor-like in fig 4, but are receptors and family of receptors. Each molecule binds on several receptors, which are identified or even sometimes not identified. Analysis of sequences of different receptors reveals that the active site of this GPCR family is kite different. The activity of the molecule if the binding part of the mechanism is well-known this some crystallographic structure, the mechanism of the biologic response is unknown. In conclusion of this remark, an analysis of site in term of residues should give a validation if site is fill with residues acceptor of electrons, an electron donor molecule should have a good binding.

Authors’ reply

As we already explained previously, the main objective of this investigation is to classify the antipsychotics by using intrinsic properties. It is a good idea to include residues in order to analyze the binding scheme, but this is a matter of a different investigation. The classification presented here could be very useful for future investigations and also in the clinic of these patients.

Reviewer #2:

The list of molecules studied is concise in the article. First, second, and third generations of antipsychotic drugs and agonists are more numerous than in the list of molecules. A full list is necessary to validate the assumption of agonist or antagonist drugs is correlated this the acceptor or donor of electrons. The case is more complicated than a molecule has nitrogen atom or halogen it is antagonism, and a molecule has a hydroxy function; it is an agonist.

Authors’ reply

We agree with the reviewer. There are hundreds of antipsychotics, but the drugs presented here are the ones that have been used for several years and they are very well characterized. Other drugs are not completely characterized, and others bind to several receptors, or are agonists/antagonist of other neurotransmitters. For some of these thirty antipsychotics there are theoretical studies concerning the binding site to the dopamine receptor. At this point we do not generalize the properties for agonists/antagonists but we classify these 30 molecules according to the electron/donor-acceptor properties.

Submitted filename: letterMARTINEZplosONEresponse1.docx

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14 Oct 2019

PONE-D-19-20849R1

A quantum chemistry approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease

PLOS ONE

Dear Prof. Martinez Vazquez,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Reviewer 2 requests that justification for the choice of molecules should be given.  Please give this careful consideration and revise accordingly.

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Dennis Salahub

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: All the points have been taken care of by the authors. In my opinion the manuscript is acceptable as is

Reviewer #2: The authors have an answer to previous questions. If we could agree, taking accounts the structure of receptors is hard to include in the study at this stage, the fact that one of the main actors of the interactions is missing.

On the second remark, concerning the option to take a set of well-characterized molecules, vs all molecules with molecules not well characterize is acceptable.

Nevertheless, a description of the set (30 molecules) and why each molecule is chosen is important. The point here is too validated the composition of the set and at the end the final model. The idea is too reject than it is just an ad-hoc selection of molecule which supports the clustering model.

Nevertheless, the study, which focalizes on a set of well-described ligands could be interesting for researchers in the field if the set is validated.

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Reviewer #1: No

Reviewer #2: No

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17 Oct 2019

PONE-D-19-20849

A quantum chemistry approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease

Professor Dennis R. Salahub

Academic Editor

PLOS ONE

Dear Prof. Salahub,

We thank the useful comments of both reviewers. Reviewer 2 requests the justification for the choice of molecules. We revised the manuscript accordingly, and we added the following paragraphs at the end of the Methods section.

In this investigation we analyze 20 antagonists and 10 agonists of dopamine (see Figure 1). These molecules have been selected due to the following reasons [11]. The selected First Generation Antipsychotics represent different families of compounds. Haloperidol, trifluperidol, benperidol, spiperone, pipamperone and droperidol are typical antipsychotic of the butyrophenone family. They exhibit high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. These butyrophenones have different receptor binding profiles and exhibited distinctive clinical efficacy. Haloperidol is one of the first drugs used to treat schizophrenia and it is the most commonly used. Trifluperidol is stronger than haloperidol. Benperidol and spiperone are two of the most potent antipsychotics in this family. Moreover, spiperone is used in treating drug-resistant schizophrenia. Pipamperone present a different pharmacological profile and it can be classified as a first-generation typical antipsychotic. It was considered as a forerunner of atypical antipsychotics. Chlorprothixene and clopenthixol are typical antipsychotics of the thioxanthene group. Raclopride is a selective antagonist of dopamine receptors and it can be radiolabelled and used as a tracer for in vitro imaging. Sulpiride belongs to the benzamide class. Within this group of molecules, we can compare ligands of the same family and also ligands from different families.

The First Generation Antipsychotics have largely given way to Second Generation Antipsychotics such as risperidone, clozapine, olanzapine, quetiapine and ziprasidone. Clozapine was the first antipsychotic of the second generation that was synthesized and tested. It has antipsychotic action but no Parkinson-like motor side effects and it is one of the most widely used together with risperidone. Clozapine is the most efficacious antipsychotic drug and it is used only for treatment of resistant schizophrenia due to its severe side effects. Olanzapine has a similar structure and it is also a good antipsychotic but with lower side effects. Risperidone, the second atypical antipsychotic quickly became a first-line treatment for acute and chronic schizophrenia because of its preferential side effect profile. Ziprasidone was also developed based upon clozapine and it is used since 1998. All these antipsychotics are widely used in the treatment of schizophrenia.

Aripiprazole and cariprazine are relatively new antipsychotic drugs and represents the Third Generation of Antipsychotics. They are dopamine system stabilizers. Finally, the agonists that we investigated were selective developed to be agonists and therefore, they are very well characterized as agonists. These molecules were investigated theoretically with docking studies that allow investigating potential sites of interaction [53].

We hope to have been able to solve and properly answered the reviewer's concerns.

Finally, we kindly would like to request if possible, a discount on the fees of this open access. Unfortunately, we do not have any funding (grants) that can cover these fees and therefore, we should pay this contribution with our own money.

With my best regards

Prof. Ana Martínez

Submitted filename: letterMARTINEZplosONEresponse2.docx

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21 Oct 2019

A quantum chemistry approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease

PONE-D-19-20849R2

Dear Dr. Martinez Vazquez,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Dennis Salahub

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

28 Oct 2019

PONE-D-19-20849R2

A quantum chemical approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease

Dear Dr. Martinez Vazquez:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

Dr. Dennis Salahub

Academic Editor

PLOS ONE