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Article

Potential Ligands to 3-Dehydroquinate Dehydratase (SaDHQD) of Staphylococcus aureus, Evaluated by Molecular Docking and In Vitro Assays to Develop an Antibiotic Drug

by
Julio Cesar Armenta-Gorosave
,
Gerson Ney Hernández-Acevedo
,
Brenda Chimal-Vega
,
Donato A. Rechy Iruretagoyena
,
Ricardo Delgadillo-Valles
* and
José Luis Vique-Sánchez
*
Facultad de Medicina y Nutrición, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
*
Authors to whom correspondence should be addressed.
Sci. Pharm. 2026, 94(3), 74; https://doi.org/10.3390/scipharm94030074
Submission received: 14 July 2026 / Revised: 23 August 2026 / Accepted: 26 August 2026 / Published: 31 August 2026
(This article belongs to the Topic Research in Pharmacological Therapies, 2nd Edition)
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Abstract

The World Health Organization (WHO) estimates that by 2050, bacterial resistance will cause 10 million deaths, of which approximately one million are associated with multidrug-resistant (MDR) microorganisms. Staphylococcus aureus is one of the bacteria with high resistance to the most widely used antibiotics that cause infections worldwide. Reports show that approximately 80% of S. aureus strains are resistant to penicillin (methicillin resistance), and that this resistance has been developing since the 1960s (WHO). On the other hand, there are new potential targets to develop new antibiotic drugs; notably, the 3-dehydroquinate dehydratase of S. aureus (SaDHQD) is relevant for this, due to the SaDHQD involved in the metabolism of the S. aureus, which is necessary in the shikimate pathway. This study proposes two compounds against SaDHQD to develop a new antibiotic drug. We performed in silico and in vitro assays for it, and in this way, this study proposes compounds that could be selected against SaDHQD, for the development of a new antibiotic drug.

1. Introduction

Humans are natural reservoirs of Staphylococcus aureus (S. aureus) [1]; however, this bacterium can also cause infections in several animal species [2,3,4,5]. S. aureus colonization has been reported in 30–50% of healthy adults, and persistent colonization following infection may occur in approximately 10–20% of individuals [6]. Colonization is also associated with an increased risk of infection and complications in individuals with underlying conditions or clinical risk factors, including diabetes, substance use disorders, hemodialysis, surgery, and human immunodeficiency virus infection.
S. aureus is associated with both hospital- and community-acquired infections [7,8], with hospitalized and immunocompromised individuals representing the principal risk groups. In 2017, methicillin-resistant S. aureus (MRSA) was estimated to account for 52% of multidrug-resistant infections among hospitalized patients in the United States. The major clinical complications included bacteremia, pneumonia, endocarditis, and vascular infections [7,9]. This burden is further exacerbated by resistance to commonly available treatments. S. aureus bacteremia has been associated with case-fatality rates of 15–30% and approximately 300,000 deaths annually [9].
Furthermore, S. aureus has been identified as the leading bacterial cause of death in 135 countries [9,10]. This global burden highlights the need to develop new therapeutic agents against this pathogen, particularly because the prevalence and diversity of resistance to currently available antibiotics have increased. Clinically relevant resistant phenotypes include MRSA and vancomycin-resistant S. aureus [6,7,11]. Common strains of S. aureus are resistant to penicillin (approximately 80%), making it necessary to use other antibiotics and their combination (aminoglycosides, oxacillin, or nafcillin) (WHO) [6]. Consequently, the development of new drugs against S. aureus has become increasingly important [12], and is consistent with Objective 3 of the United Nations Sustainable Development Goals (SDG) for 2030.
One strategy for developing new antimicrobial agents is the identification of intracellular targets involved in essential metabolic processes. In this context, the shikimate pathway represents a promising target because it is widely distributed among microorganisms, plants, and fungi but absent in mammals. This pathway is essential for the biosynthesis of chorismate, which serves as a precursor for biologically relevant compounds, including aromatic amino acids, folates, and ubiquinone [13,14]. Therefore, enzymes within the shikimate pathway constitute potential molecular targets for the development of selective antimicrobial agents with a potentially reduced risk of host toxicity.
The third enzymatic step of the shikimate pathway is catalyzed by 3-dehydroquinate dehydratase (DHQD). In S. aureus, this enzyme (SaDHQD) represents a potential target for disrupting a metabolic pathway that is important for MRSA survival [15,16]. The residues Glu35, Arg37, Arg70, Lys160, His133, Arg202, and Gln225 have been reported to contribute to SaDHQD catalytic activity [15,16] (Figure 1).
Although enzymes of the shikimate pathway have received increasing attention as potential antimicrobial targets [17,18,19], and DHQDs from other organisms have been investigated as targets for antibiotic development [20,21], relatively few studies have focused on the identification of ligands capable of inhibiting SaDHQD [11]. In contrast, various research groups have primarily employed in silico approaches to identify potential DHQD inhibitors in pathogenic microorganisms, including Mycobacterium tuberculosis [20,22,23], Clostridioides difficile [24,25], Helicobacter pylori [26], and Enterococcus faecalis [27].
In M. tuberculosis, ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077 have been identified as potential inhibitors of MtDHQD. The residues Glu20, Ile102, Val105, and Arg112 form part of the enzyme’s active site, whereas Arg15, Tyr24, Asn75, and His101 participate in ligand stabilization [20,22]; as well as for C. difficile, two compounds derived from 2,5-dichlorobenzenesulfonamide and one derivative of tetrahydrobenzo[b]thiophene-3-carboxylic acid produced ≥40% inhibition of DHQD at concentrations of 10–20 µM. These compounds were selected from a library of approximately 50,000 molecules obtained from ChemBridge Corporation and interacted with the enzyme’s active site through hydrogen bonds with Lys171. This interaction prevented closure of the β8–α8 loop, a conformational movement required for catalytic activity [24,25].
Collectively, these studies support DHQD as a potential molecular target in different pathogenic microorganisms. Nevertheless, the development and experimental evaluation of ligands targeting SaDHQD remain limited [11]. Therefore, the present study evaluated selected compounds as potential SaDHQD ligands with the aim of disrupting the shikimate pathway and reducing bacterial viability. Molecular docking was combined with in vitro assays to experimentally evaluate the computational predictions and determine their correspondence with the observed biological activity. This approach may contribute to the development of antimicrobial compounds that could serve as adjunctive agents against S. aureus strains resistant to currently available treatments [28,29].

2. Materials and Methods

2.1. Preparation of Receptor Protein and Definition of Binding Site

The X-ray crystallographic structure of SaDHQD was obtained from the Protein Data Bank (PDB) [30], PDB code 6SFH. The catalytic site region was used to perform the molecular docking [15,16] (Figure 1). The protonation and energy minimization of PDB file was performed using Molecular Operating Environment (MOE, 2024.0601) software with the default parameters, and the CHARMM27 Force Field used was [31].

2.2. Screening Library

The EXPRESS-Pick Stock small molecule screening library from ChemBridge Corp. (San Diego, CA, USA) [32] was used for molecular docking. This small molecule screening collection comprise approximately 500,000 chemical compounds that fulfill the druggable properties of Lipinski’s rules [33] and covers a wide area of chemical space.

2.3. Molecular Docking

Molecular docking was carried out by MOE, the region around the catalytic site in SaDHQD was used as protein target for a molecular docking [15,16] (Figure 1), and up to 100 conformers of each molecule (from EXPRESS-Pick Stock) were used for molecular docking. A flexible ligand–rigid receptor molecular docking was performed in Dock module in MOE, as we had reported [33,34,35,36]. Later, the values of up to 10 conformers of each compound were analyzed, and the average ΔGbinding of each molecule was determined, as previously reported [33,34]. The analysis of ligand interaction per amino acid was conducted using Protein Ligand Interaction Profiler (PLIP) [37].

2.4. Selection of the Best 16 Compounds

From the docking results, up to 10 conformers for each compound were analyzed to determine their ΔGbinding averages in order to select the best 16 compounds as previously we have reported [35,38,39] (using Excel Microsoft-365 software). The description of chemical properties and the theoretical toxicity (mutagenicity and carcinogenicity) of each compound selected were determined [40,41]. Then, the compounds were bought from ChemBridge Corp. (San Diego, CA, USA); purity reported by the manufacturer was greater than 95%, confirmed by LC/MS, and the stock solutions of each compound (10 mM) were diluted in the recommended vehicle: DMSO.

2.5. Reagents

Cell culture reagents were purchased from Thermo-Fisher (Carlsbad, CA, USA), tissue culture plates and other plastic materials were obtained from Corning Inc., and Sa1–Sa16 compounds bought from ChemBridge Corp. [32]. Purity of the compound reported by the manufacturer was greater than 95% checked by LC/MS, the stock solutions for compounds were prepared in DMSO (1–10 mM). For bacterial assays, we use strains of Staphylococcus aureus (ATCC:25923), Muller–Hinton agar (Cat. 105437, Millipore, Merck, Darmstadt, Germany), and imipenem for positive controls (Sigma-Aldrich, St. Louis, MO, USA). For cytotoxicity assays, we use DMEM and Optimem (Sigma-Aldrich, USA) buffers and Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma-Aldrich and Merck (Darmstadt, Germany).

2.6. Susceptibility Tests for Sa-1 to Sa-16 Compounds by Disk Diffusion

Antimicrobial susceptibility testing (AST) was performed adhering to EUCAST Disk Diffusion Method for Antimicrobial Susceptibility Testing Version 13.0 [42]. Mueller–Hinton agar (MHA) was the medium for disk diffusion antimicrobial susceptibility testing (AST). Antibiotic susceptibility testing was performed using the disk diffusion method [42,43,44,45]. The antimicrobial effect of the 16 acquired compounds was determined using in vitro cultures of S. aureus in 100 mL Petri dishes. The penicillin-susceptible strain of S. aureus from ATCC:25923 was used, employing 6 mm disks from one manufacturer (Cat. WHA2017006, Whatman-Cytiva, MA, USA). To determine the antimicrobial effect (susceptibility), the compounds were tested individually at concentrations at 50 and 300 µg, with imipenem (30 µg) used as control, and incubated at 35 ± 1 °C for 20 h. Each disk-strain sample was tested in triplicate (three separate inoculum suspensions) in MHA plates. All inhibition zone diameters were measured by a single technician to the nearest millimeter.

2.7. Determination of the Minimum Inhibitory Concentration (MIC) Values by the Broth Microdilution Method

The MIC for methicillin-susceptible S. aureus was determined from the best compounds identified in the disk diffusion assay [5,46]. This was done using the tryptic soy broth dilution method [46,47,48], with some modifications according to EUCAST method [49]. A two-fold dilution was performed from column 2 to column 11 by adding 5 µL (starting at a concentration of 1 mg/mL in column 2) of each compound (Sa-3 and Sa-8) to 100 µL of culture medium in the initial column. A amount of 100 µL of culture medium was placed in column 1 as a sterility control. The tested concentrations of the compounds were obtained by triplicate serial dilutions of the S. aureus bacterial suspension (ATCC:25923) with an OD600 adjusted to 0.5 McFarland in all wells containing the compound, in the imipenem, and DMSO (5 µL) control wells, yielding an approximate concentration of 5 × 105 CFU mL−1 per well. The samples were incubated at 37 °C for 24 h without shaking. After 24 h, the lowest concentration of each compound with no visible growth was considered the MIC for each isolate [5,46,49]. Experiments were performed in triplicate.

2.8. Cell Culture

The C9 cells (hepatocytes) and prostate cancer (PC3) cells from American Type Culture Collection (ATCC) were cultured in 100 mm Petri dishes with Dulbecco’s Modified Eagle’s Medium (DMEM), supplemented with 3.7 g/L sodium bicarbonate, 5% fetal bovine serum (FBS), and antibiotics in a humidified atmosphere containing 5% CO2 and 95% air at 37 °C.

2.9. Cytotoxicity Assay with PC3 and C9 Cells Cultures Determined by MTT

The MTT viability assay was performed as described previously [50,51]. These assays were for the best compounds with potential antibiotic effect. We tested compounds with PC3 and C9 cells in 96-well microplates (10,000 cells per well); they were treated for 24 h with concentrations between 7–400 µM of each compound, and DMSO at a final concentration of 0.5% (v/v) was used as vehicle control. After treatment, the media was replaced with medium containing MTT (0.5 mg/mL) for 4 h, then cells were incubated overnight with lysis buffer (50% dimethylformamide, 20% SDS; pH = 4; Sigma Aldrich, USA). Finally, the plate was read at 595 nm. The assays were performed in triplicate and in three independent studies. The percentage viability was calculated according to the formula: % viability  =  [mean optical density (O.D.) treated cells  ×  100]/(mean O.D. control cells). The concentration corresponds to 50% inhibition viability (IC50), and in this study, cytotoxic concentration 50% (CC50) measures the concentration that reduces the viability of healthy cells by 50% (toxicity). It was calculated by a non-linear regression analysis (percentage of viability vs. log concentration) using GraphPad Prism ver. 8.0 software (GraphPad, San Diego, CA, USA).

2.10. Statistical Analysis

Data’s results were expressed as mean ± standard deviation (SD) of minimum three independent experiments. The disk diffusion results were analyzed against target values and ranges in the EUCAST Tables [43]. Statistical significance, averages and CC50 were determined by GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA), and Excel Microsoft-365 software. Differences were considered statistically significant at p < 0.05.

3. Results

3.1. Selection of the Best 16 Compounds by Molecular Docking

We determined the best 16 compounds from the EXPRESS-pick Collection library from ChemBridge Corp. (approximately 500,000 compounds) [32] by molecular docking. These compounds were selected based on their average binding affinity (ΔGbinding), using 10 conformers of each compound. After classifying and analyzing all compounds, we determined a range of −7.89 to −7.31 kcal/mol for the best 16 compounds (Table 1; the details are provided in Table S1 in Supporting Information). The 16 compounds were labeled as Sa-1 to Sa-16, and each compound’s interaction with SaDHQD was analyzed using its interaction report (Table 2; the details are provided in Tables S2–S17). The ΔGbinding averages are related to the number of interactions generated from the conformers analyzed by molecular docking (mainly hydrogen bonding and hydrophobic interactions; Tables S2–S17).

3.2. Main Interactions of Sa-1 to Sa-16 Compounds with SaDHQD

From the molecular docking results, we determined the main amino acids for interactions for all compounds (Tables S2–S17) and the primary amino acids in SaDHQD that interact with compounds Sa-1–Sa-16 (Table 2). For these amino acids, the compounds showed greater interactions with Arg37, Arg70, Gly75, and Phe135 (mainly through hydrogen bonding and hydrophobic interactions). The main interactions between SaDHQD and conformers of each compound are shown in the Supporting Information (Figures S1–S16).

3.3. Antimicrobial Effect of Sa-1 to Sa-16 Compounds Determined by Disk Diffusion Method

The 16 compounds were tested at 50 and 300 µg of concentration, using 6 mm disks, and imipenem as a positive control, following the EUCAST methodology [42,43,49]. MHA plates were inoculated with the susceptible isolate of S. aureus (ATCC:25923), disks with treatments were collocated, and plates were incubated at 36 °C for 20 h (each disk-compound was tested at least in triplicate). Only then we determined an antimicrobial effect to Sa-3 and Sa-8 compounds (around 8–10 mm of zone diameter, Figure 2), with the highest concentration: 300 µg; due to these results, we continued only with Sa-3 and Sa-8 compounds.

3.4. MIC to Sa-3 and Sa-8 Compounds

The MIC of Sa-3 and Sa-8 compounds is: 500 µg/mL for methicillin-susceptible S. aureus (Figure 3). These MIC were determined by EUCAST guides [42,49], starting with a concentration of 1 mg/mL and imipenem as control.

3.5. Cytotoxicity Assay in PC3 and C9 Cells Cultures Determined by MTT

We determined the cytotoxic effect at 24 h by in vitro assays through PC3 and C9 cells cultures. We tested both compounds (Sa-3 and Sa-8) up to 400 µM, and only one compound showed a relevant cytotoxic effect: the Sa-3 compound with a CC50 of 33.1 µM (16.1 µg/mL) for C9 cells, and a CC50 of 44.7 µM (21.8 µg/mL) for PC3 cells after 24 h (Figure 4). Regarding the Sa-8 compound, after 24 h and above 100 µM of concentration (51.5 µg/mL), a moderate cytotoxic effect was observed. DMSO control was without cytotoxic effect, and all assays were made with 0.5% DMSO/vehicle (v/v).

3.6. Theoretical ADME and Toxicity Effect of Sa-3 and Sa-8 Compounds

We reported the theoretical cytotoxic effects of Sa-3 and Sa-8 compounds (Table S18) [40] and the theoretical LD50 for both compounds in “class 4” according to the GHS [52]; these results are favorable, and we reported their Absorption, Distribution, Metabolism, and Excretion (ADME) characteristics and chemical properties (Table S19), and these results are presented in the Supporting Information.

4. Discussion

As we mentioned, it is necessary to develop new antibiotics that can help address the resistance problems that have developed with current treatments that have been on the market for a long time [53,54,55]. Therefore, studying new therapeutic targets can contribute to developing new antibiotics or combinations with existing drugs. As already proposed, the shikimate pathway may be a therapeutic target [17,18,19,56,57,58]. In this study, SaDHQD is proposed as a therapeutic target, for proposing compounds that may have an effect on this enzyme and regulate its activity or function on the shikimate pathway that is essential for the proliferation of S. aureus [16]. We started by performing a molecular docking, and the selection of 16 compounds (Table 1); the interaction of them with SaDHQD was determined by molecular docking, and thus some of these compounds could be able to reduce the activity of SaDQHD, which is already widely described, and its function in the shikimate pathway [16]. Whereas, our study is different, because we are looking for a new molecule that has no previous reports of any biological effect (Table 1); it is notable that there are more developments handling Benzimidazole derivatives to reach new antibiotics against S. aureus [16,59,60]. As we mentioned, there are approaches to identify potential DHQD inhibitors, including Mycobacterium tuberculosis [20,22,23], Clostridioides difficile [24,25], Helicobacter pylori [26], and Enterococcus faecalis [27]; so, in these studies, in silico and in vitro assays were performed, identifying residues in each of these targets that are critical for ligand selectivity (Figure 5). Therefore, we propose that the observed antimicrobial effect (Figure 2) may arise from the potential interaction of compounds Sa-3 or Sa-8 with SaDHQD.
Thus, we began determining the antimicrobial effect for the 16 compounds proposed (Table 1), by disk diffusion method (EUCAST) [43]. We tested two concentrations, at 50 and 300 µg, and only the Sa-3 and Sa-8 compounds were the ones that showed a small halo (which was slightly larger at 300 µg), with a zone diameter of 8 to 10 mm for these two compounds (Figure 2). We used the established control (imipenem at 30 µg) which is required to produce a zone diameter of at least 27 mm [49]. According to EUCAST guidelines, the two drugs with the smallest inhibition zones are nitrofurantoin (at least 13 mm) and trimethoprim (at least 14 mm). Consequently, an inhibition zone of less than 10 mm suggests that Sa-3 and Sa-8 lack adequate antibacterial activity; however, these two molecules remain candidates for future consideration, particularly given their intracellular target (SaDHQD), and the potential for combination therapies. In this way, this assay clearly demonstrated the potential antimicrobial effects (Figure 2); although the antimicrobial effect seems minimal, the effect is evident for Sa-3 and Sa-8 compounds, and to continue the in vitro evaluation.
Then, regarding the MIC broth microdilution, we continued with only two compounds: Sa-3 and Sa-8. We determined the MIC at 500 µg/mL for both compounds (Figure 3); while this value remains high, it serves as a starting point for the development of a new antibiotic, especially when considering studies identifying other targets within the shikimate pathway, such as shikimate dehydrogenase [61], and which report advances in the MIC of 12 mM [62], which is far above our results.
We recognize that this study is preliminary and that further trials are required to test the effect against resistant S. aureus isolates; however, there are currently no molecules reported experimental, only in silico [11]. These two molecules are novel (Sa-3 and Sa-8), and we have already begun to demonstrate results in vitro and they could hold the key to overcoming resistance to current treatments.
To justify these results by docking results, we analyzed the main interactions of these compounds (Tables S4 and S9); both compounds with conformers interacting inside the catalytic pocket (Figure 6). Docking results showed interactions with Arg37, Arg70, Gly75, Tyr77, and Lys160 amino acids, consistent with the initial docking setup, which targeted a potential site within the catalytic region (where Lys160 is important in the catalytic site [11,63]; Figure 1). Nevertheless, it is necessary to evaluate them by other assays, for determining which is better or even which could be combined or will be an adjuvant with another antibiotic drug (like trimethoprim/sulfamethoxazole or penicillin/acid clavulanic) [53,54].
Regarding cytotoxic effects of these compounds, the Sa-8 compound is potentially secure to use in humans, and for the Sa-3 compound, we determined a moderate cytotoxicity (for C9 cells the CC50: 33.1 µM, and for PC3 the CC50: 44.7 µM). There are options to develop these potential antibiotic drugs; these results allow us to considerer options to combine with other antibiotic, synergistic effects (lower dosages); even these two molecules could serve as a basis for developing derivatives aimed at enhancing their effects. As we mentioned, we determined the theoretical toxicity [40,41] using Ames test, Boiled-egg graph, Lethal dose 50 (LD50), and ADME characteristics, thus we propose that both compounds have favorable toxicity results (Tables S18 and S19 and Figure S17). In this way, we propose that both compounds showed good experimental and theoretical toxicity results, with regard to other similar potential drugs developments (directed to targets in cytoplasm) [16,56,58].
Finaly, our research group have developed strategies to develop drugs with notable results (using molecular docking, theoretical toxicity, and ADME characteristics) [34,36,64,65], always searching new and innovative effects of molecules on new targets [38,39,66]. Signally, currently there is no reported compound that specifically could inhibit SaDHQD’s functions, but there are some developments proposing derivatives of other drugs [67,68]. Therefore, our compounds proposed show progress, such as specific drugs against SaDHQD of S. aureus; and although the antimicrobial effects are the beginning, they show a clear effect that allows us to continue advancing with this development, and it is necessary to demonstrate the selectivity between these compounds and the recombinant SaDHQD protein. This motivates us to continue seeking its validation with SaDHQD protein, and methicillin-resistant strains of S. aureus (MRSA) [5,7,11,12], and to look for combinations with other drugs, which are currently widely used to seek greater efficiency of current antibiotics (Figure 7), and thus, to be able to determine any synergistic effect like other studies [69]. We keenly recognize that the above correlation has limitations and is speculative to reach these results against some kinds of strains of S. aureus, mainly methicillin-resistant strain, and it is necessary to validate these results at least with resistant strains.

5. Conclusions

This study proposes two compounds (Sa-3 and Sa-8) with an antimicrobial effect that were developed to be selective against SaDHQD; in this way these compounds could develop them as new antibiotics against S. aureus. Thus, these compounds could be adjuvant treatments against S. aureus through a new target, the SaDHQD, but more studies will be necessary for the development of this therapeutic strategy.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/scipharm94030074/s1, The following Supporting Information provides figures and tables of interactions for compounds with SaDHQD per amino acid, that support the information given in the results and discussion.

Author Contributions

Conceptualization, J.L.V.-S., R.D.-V. and J.C.A.-G.; Methodology development, J.L.V.-S., R.D.-V., D.A.R.I., G.N.H.-A. and B.C.-V.; Validation, R.D.-V., G.N.H.-A. and D.A.R.I.; Formal analysis, J.L.V.-S., D.A.R.I., B.C.-V. and J.C.A.-G.; Resources, J.L.V.-S., R.D.-V., G.N.H.-A. and D.A.R.I.; Data curation, R.D.-V., D.A.R.I., G.N.H.-A., B.C.-V. and J.C.A.-G.; Writing—review and editing, J.L.V.-S., D.A.R.I., B.C.-V., J.L.V.-S. and J.C.A.-G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding authors.

Acknowledgments

The authors are very grateful for the scholarship granted to student Julio Cesar Armenta-Gorosave, number: 799526-SECIHTI, financial support from SECIHTI; CBF2023-2024-123, PREDEPA-UABC, and SNII-SECIHTI.

Conflicts of Interest

The authors declare no conflicts of interest.

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Scipharm 94 00074 g001
Figure 1. The structure of SaDHQD (PDB:6SFH, green) and the potential site region between the amino acids: Glu35, Arg37, Arg70, Lys160, His133, Arg202, Gln225 (Blue) are shown. This highlights the surface cavity of the proposed interaction site for the realization of molecular docking (red circle).
Figure 1. The structure of SaDHQD (PDB:6SFH, green) and the potential site region between the amino acids: Glu35, Arg37, Arg70, Lys160, His133, Arg202, Gln225 (Blue) are shown. This highlights the surface cavity of the proposed interaction site for the realization of molecular docking (red circle).
Scipharm 94 00074 g001
Scipharm 94 00074 g002
Figure 2. Results representative of disk diffusion assay, after 20 h; inhibition zone diameter between 8 and 10 mm for Sa-3 and Sa-8 compound (with 300 and 50 µg each one), and the controls are shown (imipenem and DMSO).
Figure 2. Results representative of disk diffusion assay, after 20 h; inhibition zone diameter between 8 and 10 mm for Sa-3 and Sa-8 compound (with 300 and 50 µg each one), and the controls are shown (imipenem and DMSO).
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Scipharm 94 00074 g003
Figure 3. Results of MIC assay, after 20 h of incubation. Control DMSO (Blue), imipenem + DMSO (Black), Sa-3 compound (Red), and Sa-8 compound (Green). The MIC is 500 µg/mL for both compounds.
Figure 3. Results of MIC assay, after 20 h of incubation. Control DMSO (Blue), imipenem + DMSO (Black), Sa-3 compound (Red), and Sa-8 compound (Green). The MIC is 500 µg/mL for both compounds.
Scipharm 94 00074 g003
Scipharm 94 00074 g004
Figure 4. Results of MTT assays after 24 h of incubation. (A) Results with PC3 cells, Sa-3 compound with relevant cytotoxicity, and no cytotoxicity to Sa-8 compound; (B) results with C9 cells (hepatocytes) Sa-3 compound with relevant cytotoxicity, and no cytotoxicity to Sa-8 compound.
Figure 4. Results of MTT assays after 24 h of incubation. (A) Results with PC3 cells, Sa-3 compound with relevant cytotoxicity, and no cytotoxicity to Sa-8 compound; (B) results with C9 cells (hepatocytes) Sa-3 compound with relevant cytotoxicity, and no cytotoxicity to Sa-8 compound.
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Scipharm 94 00074 g005
Figure 5. Representation of studies on inhibitors of the shikimate pathway. The specific amino acid region targeted for probable inhibition by the developed ligand is shown, in order to account for the observed antimicrobial effect.
Figure 5. Representation of studies on inhibitors of the shikimate pathway. The specific amino acid region targeted for probable inhibition by the developed ligand is shown, in order to account for the observed antimicrobial effect.
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Scipharm 94 00074 g006
Figure 6. Main interactions of compounds, in the catalytic region with Arg37, Arg70, Gly75, and Tyr77 amino acids, and it shows the protein surface. (A) Sa-3 compound (green) interacting in the catalytic region; and (B) Sa-8 compound (pink) interacting in the catalytic region.
Figure 6. Main interactions of compounds, in the catalytic region with Arg37, Arg70, Gly75, and Tyr77 amino acids, and it shows the protein surface. (A) Sa-3 compound (green) interacting in the catalytic region; and (B) Sa-8 compound (pink) interacting in the catalytic region.
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Figure 7. The main sites effects of antibiotics; the Sa-3 and Sa-8 compounds are shown in red.
Figure 7. The main sites effects of antibiotics; the Sa-3 and Sa-8 compounds are shown in red.
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Table 1. ID ChemBridge Corp., PubChem CID, and structure of the 16 selected compounds, Sa-1 to Sa-16.
Table 1. ID ChemBridge Corp., PubChem CID, and structure of the 16 selected compounds, Sa-1 to Sa-16.
Sa-1, 5175499, CID: 54680680
Scipharm 94 00074 i001		Sa-2, 5122054, CID: 2828915
Scipharm 94 00074 i002
Sa-3, 7107702, CID: 2926445
Scipharm 94 00074 i003		Sa-4, 5548678, CID: 2851727
Scipharm 94 00074 i004
Sa-5, 7990943, CID: 2984491
Scipharm 94 00074 i005		Sa-6, 7496443, CID: 2941072
Scipharm 94 00074 i006
Sa-7, 5552746, CID: 2852034
Scipharm 94 00074 i007		Sa-8, 7980128, CID: 2981047
Scipharm 94 00074 i008
Sa-9, 5479532, CID: 2848446
Scipharm 94 00074 i009		Sa-10, 6498387, CID: 2292162
Scipharm 94 00074 i010
Sa-11, 7963059, CID: 2975447
Scipharm 94 00074 i011		Sa-12, 7960714, CID: 2974771
Scipharm 94 00074 i012
Sa-13, 5181121, CID: 2832141
Scipharm 94 00074 i013		Sa-14, 5224108, CID:2834934
Scipharm 94 00074 i014
Sa-15, 5748080, CID: 2866443
Scipharm 94 00074 i015		Sa-16, 5529494, CID: 2850201
Scipharm 94 00074 i016
Table 2. Compound ID, PubChem CID, SMILES, interaction with amino acids in SaDHQD, number of conformers used and ΔGbinding average (kcal/mol) with standard deviation.
Table 2. Compound ID, PubChem CID, SMILES, interaction with amino acids in SaDHQD, number of conformers used and ΔGbinding average (kcal/mol) with standard deviation.
Compound ID and PubChem CIDSMILESInteraction with Residues in SaDHQD (Tables S2–S11)Number of ConformersAverage of
ΔGbinding and SD
Sa-1
CID: 54680680		CC(=O)C1=CC(=CC(=C1O)C[N+](C)(C)CCOC2=CC=CC=C2)Cl.C1=CC=C2C=C(C(=CC2=C1)C(=O)O)[O−]Glu35, Arg37, Arg70, Gln74, Gly75, Asp102, Lys160, Met194, Arg202, Gln22110−7.89 ± 2.26
Sa-2
CID: 2828915		C1C[N+]2(CCN1CC2)CC3=CC=CC=C3Glu35, Arg37, Arg70, His133, Ile192, Met194, Arg202, Tyr21410−7.84 ± 1.63
Sa-3
CID: 2926445		CC(C)C1=CC=C(C=C1)OCC(=O)NCC2=CC(=CC=C2)CNC(=O)COC3=CC=C(C=C3)C(C)CArg37, Arg70, Gly75, Phe13510−7.69 ± 0.25
Sa-4
CID: 2851727		CCC(=O)NC1=CC=C(C=C1)C(=O)NC2=CC=C(C=C2)S(=O)(=O)C3=CC=C(C=C3)NC(=O)C4=CC=C(C=C4)NC(=O)CCGly75, His132, Phe135, Gln221, Pro223, Gly22410−7.64 ± 0.23
Sa-5
CID: 2984491		COC1=C(C=C(C=C1)CNC2=NN(C(=N2)NCC3=CC(=C(C=C3)OC)OC)C(=O)C4=CC=C(C=C4)[N+](=O)[O−])OCArg37, Lys72, Phe135, Gln221, Pro22310−7.63 ± 0.32
Sa-6
CID: 2941072		COC1=CC=C(C=C1)OCC(=O)NCC2=CC(=CC=C2)CNC(=O)COC3=CC=C(C=C3)OCArg37, Lys72, Phe135, Gln221, Pro22310−7.61 ± 0.11
Sa-7
CID: 2852034		CCN(CC)C(=O)CCCCCN1C(=O)/C(=C\2/C(=O)N(C(=S)S2)CCCCCC(=O)N(CC)CC)/SC1=SArg37, Arg70, Gly75, Tyr77, His133, Phe135, Lys160, Gln22110−7.60 ± 0.33
Sa-8
CID: 2981047		CC1=CC=C(C=C1)NC2=NC(=NC(=N2)OC3=NN=C(C=C3)OCCOC4=CC=CC=C4C)N5CCOCC5Ala11, Arg37, Tyr77, Lys160, Ala22210−7.49 ± 0.50
Sa-9
CID: 2848446		CCCOC1=CC(=C(C=C1C#CC#CCN2CCCCC2)C#CC#CCN3CCCCC3)OCCC.Cl.ClLeu73, Phe135, Met16410−7.45 ± 0.15
Sa-10
CID: 2292162		CC1=C(C=C(C=C1)OCC(=O)NCC2=CC(=CC=C2)CNC(=O)COC3=CC(=C(C=C3)C)C)CArg37, Arg70, Gly75, Tyr21410−7.43 ± 0.36
Sa-11
CID: 2975447		CC(C(=O)NCCC1=CC(=C(C=C1)OC)OC)SC2=NN=C(N2C3=CC=CC=C3)NC4=CC=CC=C4Arg37, Arg70, Gly75, Tyr77, Pro22010−7.38 ± 0.42
Sa-12
CID: 2974771		CS(=O)(=O)N(CC(=O)NC1=CC=CC=C1C(=O)NCC2=CC=CO2)C3=CC=C(C=C3)OCC4=CC=CC=C4Arg70, Lys72, Gly76, Tyr77, Lys160, Pro22010−7.37 ± 0.27
Sa-13
CID: 2832141		C1=CC=C2C(=C1)C=CC=C2C(=O)NC3=CC=C(C=C3)C4=NC5=C(N4)C=C(C=C5)C6=NC7=C(N6)C=C(C=C7)NC(=O)C8=CC=CC9=CC=CC=C98Gly75, Phe135, Glu136, Lys196, Gly224, Gln225, Ile22610−7.35 ± 0.15
Sa-14
CID:2834934		CC(C)(C)C(=O)NC1=CC=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(=O)O)NC(=O)C3=CC=C(C=C3)NC(=O)C(C)(C)CLys72, Tyr72, Phe13510−7.34 ± 0.14
Sa-15
CID: 2866443		COC1=C(C=C(C=C1)/C=N/NC(=O)CSC2=NN=C(N2C3=CC=CC=C3)C4=CC(=C(C(=C4)OC)OC)OC)OCGlu35, Arg37, Gly75, Glu136, Pro22310−7.32 ± 0.50
Sa-16
CID: 2850201		COC1=C(C=C(C=C1)NC(=O)NCCCCCCNC(=O)NC2=CC(=C(C=C2)OC)OC)OCGlu35, Arg37, Gly75, Lys160, Gln221, Pro22310−7.31 ± 0.31
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MDPI and ACS Style

Armenta-Gorosave, J.C.; Hernández-Acevedo, G.N.; Chimal-Vega, B.; Rechy Iruretagoyena, D.A.; Delgadillo-Valles, R.; Vique-Sánchez, J.L. Potential Ligands to 3-Dehydroquinate Dehydratase (SaDHQD) of Staphylococcus aureus, Evaluated by Molecular Docking and In Vitro Assays to Develop an Antibiotic Drug. Sci. Pharm. 2026, 94, 74. https://doi.org/10.3390/scipharm94030074

AMA Style

Armenta-Gorosave JC, Hernández-Acevedo GN, Chimal-Vega B, Rechy Iruretagoyena DA, Delgadillo-Valles R, Vique-Sánchez JL. Potential Ligands to 3-Dehydroquinate Dehydratase (SaDHQD) of Staphylococcus aureus, Evaluated by Molecular Docking and In Vitro Assays to Develop an Antibiotic Drug. Scientia Pharmaceutica. 2026; 94(3):74. https://doi.org/10.3390/scipharm94030074

Chicago/Turabian Style

Armenta-Gorosave, Julio Cesar, Gerson Ney Hernández-Acevedo, Brenda Chimal-Vega, Donato A. Rechy Iruretagoyena, Ricardo Delgadillo-Valles, and José Luis Vique-Sánchez. 2026. "Potential Ligands to 3-Dehydroquinate Dehydratase (SaDHQD) of Staphylococcus aureus, Evaluated by Molecular Docking and In Vitro Assays to Develop an Antibiotic Drug" Scientia Pharmaceutica 94, no. 3: 74. https://doi.org/10.3390/scipharm94030074

APA Style

Armenta-Gorosave, J. C., Hernández-Acevedo, G. N., Chimal-Vega, B., Rechy Iruretagoyena, D. A., Delgadillo-Valles, R., & Vique-Sánchez, J. L. (2026). Potential Ligands to 3-Dehydroquinate Dehydratase (SaDHQD) of Staphylococcus aureus, Evaluated by Molecular Docking and In Vitro Assays to Develop an Antibiotic Drug. Scientia Pharmaceutica, 94(3), 74. https://doi.org/10.3390/scipharm94030074

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