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Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-Cov-2 Activities

Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-Cov-2 Activities

Chemoinformatic analysis of psychotropic and antihistaminic drugs in the light of experimental anti-SARS-CoV-2 activities

Villoutreix BO1*, Krishnamoorthy R2, Tamouza R2, Leboyer M2, Beaune PH3,

1INSERM 1141, NeuroDiderot, Université de Paris, Hôpital Robert-Debré, F-75019 Paris, France

2Université Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-psychia- trie translationnelle, AP-HP, Département Medico-Universitaire de Psychiatrie et d’Addictologie (DMU ADAPT), Hôpital Henri Mondor, Fondation FondaMental, F-94010 Créteil, France

3INSERM U1138 Centre de recherche des Cordeliers 75006 Paris, and Université de Paris, Paris, France

* Corresponding author: [email protected]

Abstract

There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. We proposed before summer 2020 that cationic amphiphilic psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection based upon clinical observations. At that time, experimental data on SARS-CoV-2 were missing but today, open high-throughput screening results are available at the NCATS COVID19 portal. We here revisit our hypothesis in the light of these data and propose that several cationic amphiphilic psychotropic and antihistaminic drugs could be valuable to protect people from SARS-CoV-2 infection, they should have very limited adverse effects and could possibly be used as prophylactic drugs. Recent studies also suggest that some of these molecules could be of interest in more advanced stages of the disease progression. Clinical trials are now needed to fully evaluate the potentials of these molecules.

Keywords: chemoinformatics, Covid-19, high-throughput screening, , prophylaxis

Highlights

Early 2020, based upon clinical observations, we suggested that some psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection

At that time, most relevant molecules were found to be cationic amphiphilic drugs

The initial reasoning was based on previously published in vitro bioactivity data reported for various viruses but not for SARS-CoV-2

Open SARS-CoV-2 high-throughput screening data and literature mining allow for the reinvestigation of our initial hypothesis

Numerous psychotropic and antihistaminic cationic amphiphilic drugs are indeed active in vitro on SARS-CoV-2 and some studies suggest that they could also act in vivo

Many of these CADs have in limited secondary effects, some could be repositioned to protect the general population from SARS-CoV-2 infection while some might be valuable in more advanced stages of the disease progression

It is now urgent to investigate these molecules in clinical settings, even more so considering the new and upcoming variants

2 1. Introduction

Rapid pandemic spread of SARS-CoV-2 virus and the resulting COVID-19 caused havoc worldwide and continue to do so with transmission rate spikes. Hence there is an urgent need to identify potential pharmacological prophylactic/therapeutic interventions both to prevent SARS- CoV-2 infection and to improve the clinical outcome of COVID-19 patients. At present, only vaccines offer hope but small molecules interfering with SARS-CoV-2 infection would have an added value and could be cost effective. The shortest path to discover such compounds is via drug repurposing approaches but it should be mentioned, as reported by Edwards [1] that drug repurposing seldom works in Human if there are no clinical observations as background rationale and/or in the absence of a reasonable mechanistic hypothesis. Early 2020, we hypothesized, based upon clinical observations made in several hospitals including the large psychiatric department of the Henri Mondor hospital, Créteil (Paris area), France, and confirmed in several other hospitals, that therapeutic molecules used in the treatment of psychiatric patients might have protected them from SARS-CoV-2 infection and hence explained the paucity of admission to specialized COVID units [2]. In order to gain knowledge about the putative molecules that could be repositioned against SARS-CoV-2, we collected a list 18 compounds most commonly prescribed in the in- and out-patient Henri Mondor treatment programs (, Amisulpride, Aripiprazole, , Citalopram, , , Diazepam, Escitalopram, , Lithium, Lorazepam, Melatonin, Nicotine, , , Valproate, and Zopiclone). Some of these compounds belong to the phenothiazine class (e.g., Alimemazine and Cyamemazine), others contain a core (e.g., Lorazepam) or else are drugs with, for example, a core group (e.g., Cetirizine and Hydroxyzine). We investigated further these 18 drugs using chemoinformatic strategies and via literature mining as it is well documented that some molecules from these classes possess in vitro antiviral activities (reviewed in [3]). Indeed, ten out of our 18 drugs have been reported to have in vitro antiviral activities against various types of viruses including HIV, Ebola, HSV, MERS or SARS. Four were chemically close to molecules that display such in vitro antiviral activity and were therefore predicted to also possess such property based on “principle of similarity” commonly applied in medicinal chemistry. While the psychotropic and antihistamine drugs that we were investigating belong to several chemical families, we observed a common trend among these molecules. Eleven (60%) out of these 18 most prescribed compounds were cationic amphiphilic drugs (CADs). CADs are molecules characterized by the presence of a hydrophobic-aromatic ring system and a side chain that carries one (or more) ionizable amine functional group(s) (i.e., a basic moiety). Many such compounds accumulate in or in other acidic subcellular compartments (i.e., lysosomotrophic agents, a well-known molecule acting on SARS-CoV-2 in vitro at least via this

3 mechanism, among others, is the antimalarial drug hydroxychloroquine). Many CADs are therefore known to interfere with intracellular trafficking (e.g., endosomal entry route, clathrin- mediated or not) and several such molecules have indeed in vitro antiviral activity ([4, 5]). CADs compounds are also known to induce phospholipidosis in vitro (a lysosomal storage disorder), and 14 out of our list of 18 drugs were known or predicted to induce phospholipidosis [6]. These molecules are associated with intracellular traffic perturbations and could play a role in SARS- CoV-2 infectivity [7].

From these observations, presumably, many of our 18 molecules could play a role in the early phases of virus life cycle. In short, early 2020, our hypothesis was that interesting compounds to reposition against SARS-CoV-2 would be CAD psychotropic and antihistaminic molecules (i.e., the ones present in our list of 18 compounds or analogs that possess similar physicochemical properties and chemical substructures, in our list of 18 compounds). These drugs could perturb virus entry, for instance by interfering with normal endocytosis but could also inhibit directly or indirectly the interaction between the viral Spike protein and the host ACE2 receptor (details about cell entry mechanisms are reported here [8]). These drugs obviously bind to their primary targets (for example histamine receptors, dopamine receptors, GABA(A) receptor) although the impact of such interactions on COVID-19 is not clear. In addition, it is well-known that drugs can interact with several targets and as such the CAD psychotropic and antihistaminic molecules are likely to also bind to known (e.g., the Sigma receptors [9]) and unknown off-targets and act on the virus and/or on the host defense mechanisms. The conclusion of our first analysis was that CAD psychotropic and antihistaminic molecules could confer protection against SARS-CoV-2 infection in psychiatric patients as these subjects receive as treatment a “CAD cocktail” that certainly interferes with the endo-lysosomal viral machinery essential for cell entry, replication and spread to other cells [2] while some compounds (e.g., antihistamine drugs) could also down-regulate prominent inflammatory messengers [4, 10]. Yet, in our first report, we also mentioned that while such drugs might protect against SARS-CoV-2 infection, many of them do have concerns (e.g., toxic side effects if unmonitored) and hence cannot be recommended for mass population prophylaxis and/or treatment in the urgent fight against COVID-19.

When we reported our study about the possible protective potentials of psychotropic and antihistamine drugs against SARS-CoV-2 infection [2], in vitro data on SARS-CoV-2 were not available. Since then, low-throughput and high-throughput screening experiments have been performed (see a recent review [11]). To the best of our knowledge, the largest high-throughput screening data open to the research/medical community is available at the NCATS COVID19

4 portal (https://opendata.ncats.nih.gov/covid19). These data involve the screening of over 10,000 chemical compounds. We here investigate our initial observations in the light of these new experimental data. We thus further rationalize the potential protective effect of some psychotropic and antihistamine drugs against SARS-CoV-2 infection and propose some already approved drugs (with manageable/tolerable adverse effects) that could be repositioned to protect the general population against COVID-19.

2. Materials and methods 2.1 Data preparation and analysis The first step involved the curation and preparation of the experimental screening data. We downloaded the data on SARS-CoV-2 cytopathic effect (CPE) from the NCATS COVID19 portal. This assay measures the ability of a compound to reverse the cytopathic effect induced by the virus in Vero E6 host cells (one of the most commonly used cell lines for studying this family of virus). The assay provides valuable basic information about the ability of a compound to restore the cells’ function but does not provide indication about the possible mechanism of action(s) of the small chemical compound under study. We also explored using the same Vero E6 cells the cytotoxic effect of these molecules in a counterscreen since the observed effect of some compounds may be mediated through cell viability and could lead to erroneous interpretation of the CPE results. Such information on cell viability is evidently important in the applicability of such compounds in clinical pharmacological interventions. Some additional data are important to take into account in the present analysis and involve the effect of the chemical compounds over human fibroblasts. This assay measures the host cell ATP content as a readout for cytotoxicity. When available, we annotated further the CPE data with the results of this assay. To be able to quickly repurpose a compound, we focused essentially on molecules that have been approved or are in clinical trials (in some instances drugs are only approved for veterinary use). We thus cross-linked the CPE sample ID numbers to drug names (e.g., international nonproprietary names), PubChem SID or CID numbers [12] or to ChEMBL ID numbers [13] and to molecules that possess ATC (Anatomical Therapeutic Chemical Classification system) codes and/or have documented therapeutic indications as found in DrugBank [14], DrugCentral [15] and eDrug3d [16]. Molecules that are at the preclinical stage (e.g., chemical probes) were essentially excluded via this procedure. Additionally, the salts, when present in the chemical file, were deleted using the Maya chemistry

5 toolkit [17] and the chemistry of the molecules was standardized using our FAF-Drugs4 web server [18]. The drugs in duplicate were removed. Further curation of the CPE data also involved the following: i) removal of a few molecules without potency values (AC50 values, i.e., concentration for half-maximal activity [19]), ii) investigation of the curve class (i.e., the evaluation of the quality of the dose-response curve and thus the quality of the measurements, in the CPE data, (a curve class of type 4 is a flat curve indicating no activity) and maximum response (i.e., maximum response value detected in the experiment). In such assay, compounds are usually considered active when the maximum response (absolute) value is above 30 [20]. Further, we removed molecules that were found highly cytotoxic in the Vero E6 counterscreen assay. From the initial CPE data containing 10,721 assessed samples (some molecules have been screened several times and most are chemical probes), we ended up with a list of 198 bioactive drugs. In this list of drugs, 93 were not tested for toxicity on human fibroblast and for the remaining 105 molecules, only one was found cytotoxic (Disulfiram, used for alcohol addiction, this molecule was also removed not only because of its cytotoxic nature in these assays but also as found to be a promiscuous SARS- CoV-2 main protease inhibitor [21]). At this stage of the analysis, we decided to retain all the compounds including those not annotated for human fibroblast toxicity. We then focused our attention on families of molecules that contain several members and removed some molecules with highly specific disease indication such as Deferasirox (an oral iron chelator given to patients receiving long term blood transfusions). In these last step of data curation, we grouped the 198 compounds according to chemistry and disease indications and removed molecules that did not fulfill our selection criteria. This step led to the selection of a final list of 161 molecules. Data were then visualized with DataWarrior [22]. The structural classification of chemical entities was performed using the ClassyFire application [23].

3. Results and Discussion Our selected list of 161 bioactive drugs in the CPE assay (after excluding molecules that were found to be highly cytotoxic in Vero E6 cells counterscreen assay) are prescribed as a treatment in five major disease areas (Fig. 1). Of course, it is important to note that some of the selected drugs can be given to different types of disease but we still attempted to group them into main/major indications.

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Fig. 1: Five major drug indications found to have SARS-CoV-2 cytopathic effect

Molecules that are in the “Allergies” category (different types of allergies are involved) are here all antihistamine compounds. Some of these molecules also have other properties such as anti- inflammatory effects. This group of compounds include for instance and (e.g., allergic rhinitis), (e.g., allergic and vasomotor rhinitis and allergic conjunctivitis) and (e.g., used for allergic reactions, nausea and vomiting). While not an antihistamine molecule nor a CAD, Colchicine could be present in this group although it could also be in the Cancers and Cardiovascular categories. It is an anti-inflammatory drug that could reduce the risk of complications and death from COVID-19 (communication in January 2021 by Dr. JC Tardif, Montreal Heart Institute). This molecule is not present in our list of 161 compounds because it was not active in the CPE assays that we investigated and was cytotoxic. As such, this molecule could possibly act on the exaggerated inflammatory response seen in some patients in more advance stages of disease progression.

Another major group of drugs are anti-cancer agents. Many of these compounds are kinase inhibitors such as Abemaciclib, Pazopanib, Ceritinib, Lapatinib and Imatinib. Imatinib, a potent

7 ABL inhibitor, was found here to have moderate CPE activity. This compound is in clinical trial for COVID-19 but other authors noted that this molecule had limited activity on SARS-CoV-2 entry/infection in different in vitro assay types [24]. It is also important to note that some kinase inhibitors are used for the treatment of autoimmune disorders and other complex imbalance of the immune system like for instance, Baricitinib. This compound is used for the treatment of rheumatoid arthritis and is in clinical trial for treating COVID-19 patients. Some authors suggested that it could be beneficial in preventing virus infectivity via perturbation of endocytosis [25] and/or could be important as inhibitor of targets in critically ill COVID-19 patients [26]. This compound is obviously not present in our list of anti-cancer agents and was not found active in the CPE assay. Yet, such molecule could be of interest, for instance to act on the cytokine storm. Also, in the cancer field, Pralatrexate was found able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir [27]. It is not present in our list as was found very cytotoxic but in the in vitro assays that we analyzed. Yet, this compound could be of interest.

Several drugs prescribed in the field of cardiovascular diseases were also found active in the CPE assay. These include Vorapaxar (reduces the incidence of thrombotic cardiovascular events or with peripheral arterial disease, a molecule proposed as potentially interesting for the treatment of COVID-19 patients [28]), (treatment of heart failure, hypertension, a molecule also suggested in the literature as potentially beneficial for COVID-19 patients via several mechanisms of action [29]) or Nicardipine (antihypertensive properties effective in the treatment of angina and coronary spasms).

The molecules that belong to the “Infectious Disease” category include molecules with widely different types of activities. For instance, Mefloquine and Chloroquine (anti-parasitics for Malaria), Letermovir (for prophylaxis of cytomegalovirus infection), Cenicriviroc (under clinical trials for the treatment of HIV-infection/AIDS), Nitazoxanide (broad-spectrum anti-infective drug) and Lopinavir (in the treatment of HIV-infection). Several antimalarial drugs (e.g., ) are known to act in vitro on SARS-CoV-2 [30] while the in vitro activity of Cenicriviroc has also been recently reported [31]. In the present study however, Methylene blue was not kept in our final list of 161 compounds as the molecule was reported to be cytotoxic in the NCATS COVID19 results. Nitazoxanide was for example found promising in its ability to hinder the replication of a

8 SARS-CoV-2 isolate [32] and is now in several clinical trials either alone (e.g., [33]), against placebo, or in combination with for instance Ivermectin (a broad-spectrum anti-parasite medication that was not found to be active in the CPE assays that we investigated here and that was highly cytotoxic in Vero E6 cells counterscreen).

Molecules of the “Psychotropic drugs” category also involve structurally diverse compounds that include, for instance, (an , also reported in a very recent study [34]), (an that has activity in vitro and is in clinical trial [35-37]), (an antidepressant), and Haloperidol (an antipsychotic).

From these first analysis, it was then important to cluster the small molecules based on their chemistry. Many different approaches can be used for this purpose [38] but as the bioactive compounds investigated here tend to belong to a limited number of chemical classes, a simple way is to group the compounds based on the presence of identical/similar organic functional groups. We investigated our list of 161 molecules using this strategy with the DataWarrior application. The results are shown in Fig. 2.

9 Fig. 2: Bioactive compounds (161 molecules) clustered according to the presence of organic functional groups. The molecules that were found to share identical or similar organic functions are connected by lines. The compounds are marked either as a circle (molecules not toxic in human fibroblast toxicity assay) or as a square (molecules not tested for such toxicity). The marker symbols and the connecting lines are color coded according to the reported experimental potency (AC50) values. The background colors behind the markers and lines are color coded according to the disease categories. Yet, as some compounds in the category of “Allergies” are also prescribed in psychiatric settings (indeed some psychotropic drugs were initially used as antihistaminics), we applied the same background color for these two categories to facilitate the reading of this figure.

As can be seen, a large cluster involves drugs used for allergies and for mental disorders. These molecules all share a phenothiazine group with different types of side chains (molecules around Trimeprazine also named Alimemazine or around or , a piperazine ring phenothiazine). Other molecules that are chemically closely related involve for instance Clomipramine or . Here, the phenothiazine group is not present but a group is found instead.

Earlier we suggested that cationic amphiphilic psychotropic and antihistamine drugs might play a significant protective role as witnessed by the relatively low representation of the psychiatric patients among the COVID-19 clinical units [2]. The notion of CADs and/or lysosomotropic active agents is not clearly defined but in general, the scientific community considers that the cationic character of a molecule can be flagged by the (predicted) value of its highest basic pKa while the amphiphilicity can be estimated by (computed) log P values [4, 39]. Such compounds contain organic bases with basic pKa above 6 or 7 and are expected to carry one or more positive charges at physiological pH (even more so in the acidic environment of the endosomal-lysosomal system) while the computed log P value of these molecules is in general above 3. If we apply such criteria to our list of 161 molecules, 125 compounds have a computed log P above 3 and among these, 105 have at least one positive charge, suggesting that about 65% of the compounds could be of CADs. Obviously such global physicochemical properties are present in a variety of drugs that act in many therapeutic areas. Here we found such compounds in all the five disease categories reported in Fig. 1.

From our analysis, the types of chemical structures or substructures that would seem interesting to interfere with SARS-CoV-2 infection are illustrated in Figure 3. According to the automated

10 structural classification package ClassyFire, the main chemical classes involve molecules that contain as a core a phenothiazine group (e.g., Promazine), a group (e.g., Imipramine), a benzodiazepine group (e.g., Clozapine), a group (e.g., ), a benzocycloheptapyridine group (e.g., Desloratadine), a diazanaphthalene group (e.g., Azelastine) or a and substituted derivative group (e.g., or , in this case a piperazine ring is present in the core region).

Fig. 3: The types of chemistry that could interfere with the SARS-CoV-2 life cycle in vitro following our clinical, the experimental high throughput data and chemoinformatics analysis. The largest family of molecules contain a phenothiazine group (16 molecules have such a group).

In vitro data alone cannot in general predict if a molecule is going to be active on SARS-CoV-2 in vivo. Yet, interestingly, after mining 219,000 digital health records, Reznikov et al. [40], have reported that prior usage of Loratadine, , Cetirizine, Hydroxyzine or Azelastine was associated with a reduced incidence of positive SARS-CoV-2 test results in individuals of 61 years and above. Loratadine and Azelastine are present in our list of 161 drugs. Loratadine and Azelastine were also found in other reported experimental screening data available at the open NCATS portal to perturb virus entry via modulation of the ACE2-Spike protein interaction (similar

11 results in this assay were apparently not found for Desloratadine). Diphenhydramine was not tested in the data that we downloaded from the NCATS portal but the highly similar molecule Bromodiphenhydramine was found active in the CPE assay. Also, Reznikov et al. reported that Diphenhydramine was indeed active in vitro. Hydroxyzine and its active metabolite Cetirizine, were not found active in the CPE assays that we analyzed nor in other assays reported at the open NCATS portal but Hydroxyzine was found to impede the interaction between the viral Spike protein and the human receptor ACE2 and as such could interfere with virus entry (action at the level of the Spike could also be of importance for SARS-CoV-2 virulence). In our hands, Hydroxyzine has only moderate in vitro activity (unpublished data) but we listed it as a very interesting CAD [2]. In fact very recent and interesting clinical observations suggest that Hydroxyzine could reduce mortality in patients hospitalized for COVID-19 most likely in part due to anti-inflammatory properties [41]. These data suggest that additional investigations are needed for this compound to fully understand the molecular mechanisms at play and fully assess its activity on the virus and on the host. Along the same line and with the idea of drug combination, it seems possible that the use of two anti-histamine molecules, Cetirizine and Famotidine (not predicted to be CAD), both found to be inactive in the analyzed CPE assays, might be a safe and effective approach to reduce the severity of COVID-19, presumably via a modulation of the histamine-mediated cytokine storm [42]. Overall, the present analysis, together with recently reported studies by other groups, support our initial observation [2] and do indeed suggest that “some” psychiatric patients could have been protected by their pharmacological treatments. Along this line of reasoning, it should also be mentioned that these patients receive in general a cocktail of drugs (psychotropic and anti- histamine molecules) including several CAD compounds possibly working on different molecular mechanisms.

4. Conclusions From the above analysis, we suggest that some antihistamine and psychotropic CADs could protect Humans from SARS-CoV-2 infection while some of these drugs might be also beneficial at more advanced stages of the disease. Not only recent publications mentioned above but also recent reviews suggest that more and more are research teams in different countries believe, based on different types of data, that these molecules could have a potential (e.g., some new reviews [43-

12 46]). The types of CAD molecules analyzed here have moderate to relatively high levels of anti- viral activity at nontoxic concentrations in vitro. For these reasons, some of these compounds are actively investigated such as Fluoxetine (e.g., treatment of depression) [47] or Chlorpromazine [35, 48] but many others need to be explored. The molecular mechanisms involved are likely to be complex, from perturbation of endocytosis, membrane fusion to direct binding to some specific receptors. For example, a recent investigation applied surface plasmon resonance to study some antipsychotic drugs and reported that several compounds could bind directly to ACE2 and partially inhibit this virus entry mechanism [49]. It is of course important to note that psychotropic compounds can induce side effects and might not be safe enough to be prescribed for prophylaxis to a population not concerned by psychiatric issues. Yet, with regard to SARS-CoV-2 infection, psychotropic CADs could be replaced by antihistamine CADs. Clinical trials are now needed to investigate the true potentials of these molecules in Human, the type of patients that could benefit from these molecules and at which stage of the infection the drug(s) should be given, prophylaxis being a potential option. In fact, for prevention purposes, molecules that have moderate in vitro activity might be sufficient while it is also known, that, if needed, most antihistamine CADs could be tolerated at higher doses without inducing severe side effects. Most likely, drug combinations could be beneficial but here also clinical trials will be needed to evaluate potential additivity, synergy or antagonism. Efforts on small molecule discovery are not sufficient in many countries including France while are strongly needed considering the possible emergence of devastating variants.

Contributors BV planed, generated, analyzed the chemical data and wrote a first draft of the manuscript. ML provided clinical observations. BV, RK and PB optimized the initial draft; a final version was produced by all authors.

Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could influence the work reported in this paper.

Acknowledgements We thank the foundation FondaMental for supports.

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