Acne vulgaris is a prevalent skin disorder that affects both adolescents and adults and has a major psychological impact. Antibiotic resistance is one issue that current therapies, including antibiotics, must address. A viable approach is to target Cutibacterium acnes, a crucial bacterium in the development of acne. An antibiotic of the tetracycline class called sarecycline shows efficacy despite resistance and adverse effect issues. The purpose of this study is to develop, assess, and compare the efficacy of Sandracopimar (Pimarane diterpenoids) compounds and Sarecycline in the treatment of acne by targeting the 30S ribosomal subunit of Cutibacterium acnes. Sarecycline’s binding affinity and PheSA score were assessed at the 30S ribosomal subunit binding site of Cutibacterium acnes. There were distinct interactions between Sarecycline and the ribosomal subunit, including hydrophobic and hydrogen bonding. Sarecycline demonstrated a strong binding affinity (-8.2 kcal/mol) and a PheSA score of 0.53184 within the Cutibacterium acnes 30S ribosomal subunit binding site. Sandaracopimar-15-ene-6.beta.,8.beta.-diol exhibited a binding affinity of -7.3 kcal/mol and PheSA score of 0.37252. Compound 1, a novel compound derived from Sandaracopimar-15-ene-6.beta.,8.beta.-diol, showed a slightly higher binding affinity (-8.3 kcal/mol) than Sarecycline. The molecular dynamics simulation results reveal that Compound 1 exhibited stability during a specific phase, indicating favorable binding potential with the Cutibacterium acnes 30S ribosomal subunit drug target. The compound demonstrated structural flexibility, advantageous for molecular interactions. The study indicates that Sandracopimar-derived compounds, including Compound 1, show comparable parameters to Sarecycline, suggesting similar activity in targeting the Cutibacterium acnes 30S ribosomal subunit. These compounds may serve as a potential source of novel anti-acne compounds.

Cutibacterium acnes, Sandracopimar, Sarecycline, PheSA score, Acne Vulgaris

Terpenoids are one of the largest and most structurally varied classes of naturally occurring molecules. They are a group of organic compounds made up of many isoprene (C5) structural units from mevalonic acid (MVA). Terpenoids are abundant in nature and come in a variety of shapes and forms. Mainly obtained from plants, over 50 000 terpenoids have been discovered to date (Li-chao et al. 2017; Yang et al. 2020). Pimarane compounds constitute a class of diterpenoid compounds obtained from plants and fungi but are also present in insects, microorganisms and bacteria. These compounds have been highlighted for their several reported benefits in managing various conditions (Hawksworth 1984; Reveglia et al. 2018). Most especially, Pimarane diterpenoids are known for their antimicrobial activity against gram-positive and gram-negative bacteria (Pandey et al. 2022).

Cutibacterium acnes is a gram-positive bacterium that commonly causes Acne Vulgaris. Although it is mostly found in the sebum-rich pilosebaceous units, the lipophilic anaerobic bacterium is also found in nonsebaceous regions (Ahle et al. 2023). Acne Vulgaris is a common skin condition prevalent in individuals between the ages of 12 and 24 years and can also persist in ages above this age group. Characterized by the inflammation of the pilosebaceous units, it presents with various skin lesions such as comedones (blackheads and whiteheads), papules, pustules, nodules, and cysts (Asai et al. 2016; Zaenglein et al. 2016).

The Cutibacterium acnes 30S ribosomal subunit plays a crucial role in the development of drugs against Acne Vulgaris (Dréno et al. 2018). The 30S ribosomal subunit is an essential component of the bacterial ribosome responsible for protein synthesis. Targeting this specific subunit can disrupt bacterial protein production and ultimately inhibit bacterial growth, including Cutibacterium acnes (Wilson, 2014).

By targeting the 30S ribosomal subunit, drugs can specifically inhibit the protein synthesis machinery of Cutibacterium acnes. This leads to the suppression of bacterial growth and proliferation, reducing the population of bacteria on the skin (Eady and Cove 2003). Cutibacterium acnes is associated with the development of inflammation in Acne Vulgaris and has shown increasing resistance to conventional antibiotics used in acne treatment (Thiboutot et al. 2009). Targeting the 30S ribosomal subunit provides an alternative approach that may overcome antibiotic resistance mechanisms. This is because the ribosomal subunit is an essential and highly conserved component of bacterial cells, making it less prone to developing resistance (Walsh et al. 2016). By specifically targeting the Cutibacterium acnes 30S ribosomal subunit, drugs can disrupt bacterial growth, reduce inflammation, prevent antibiotic resistance, and provide a more targeted and effective treatment for Acne Vulgaris (Thiboutot et al. 2006). However, it is important to note that the development of such drugs requires careful research, testing, and consideration of potential side effects and resistance mechanisms.

Sarecycline is a tetracycline-class antibiotic that specifically targets the 30S ribosomal subunit of Cutibacterium acnes (Leyden et al. 2018). It exerts a modulatory role in the management of Acne Vulgaris by inhibiting bacterial protein synthesis and exerting anti-inflammatory effects (Moore et al. 2018). Sarecycline binds to the 30S ribosomal subunit of Cutibacterium acnes and prevents the attachment of transfer RNA (tRNA) to the ribosome (Swetter et al. 2019). This inhibits the synthesis of bacterial proteins, leading to a disruption in bacterial growth and replication. By targeting the ribosomal subunit, Sarecycline interferes with the essential process of protein production, ultimately reducing the population of Cutibacterium acnes. Sarecycline has an extended half-life compared to other tetracycline antibiotics, allowing for once-daily dosing. This prolonged presence in the body enhances its effectiveness against Cutibacterium acnes, leading to sustained antimicrobial activity throughout the day (Eichenfield et al. 2013; Zagórska-Dziok and Sobczak 2020).

While Sarecycline has shown potential in the management of Acne Vulgaris, it’s important to consider the potential downsides associated with its use. Sarecycline is an antibiotic, and the long-term use of antibiotics in acne treatment can contribute to the development of antibiotic resistance (Bowe and Shalita 2008). Prolonged and widespread use of Sarecycline may lead to the emergence of resistant strains of Cutibacterium acnes, making it less effective over time. This can limit treatment options and pose challenges in managing acne in the future (Dréno et al. 2004). While Sarecycline is generally well-tolerated, like other antibiotics, it can have potential side effects. Common adverse effects include gastrointestinal symptoms such as nausea, diarrhea, and abdominal pain. Less frequently, it may cause photosensitivity, dizziness, and headache. Patients may also experience allergic reactions or hypersensitivity to Sarecycline (Leyden et al. 2018). Hence, the need for more potent and safer alternatives in the treatment of Acne Vulgaris.

The aim of this study is to design, evaluate and compare the activity of Sandracopimar (Pimarane diterpenoids) compounds with Sarecycline in targeting Cutibacterium acnes 30S ribosomal subunit in the treatment of acne.

Firstly, the binding affinity and pharmacophore enhanced shape alignment score of sarecycline within the binding site of the Cutibacterium acnes 30S ribosomal subunit is described. The binding affinity is a measure of the strength of the interaction between the ligand (Sarecycline) and the target molecule (Cutibacterium acnes 30S ribosomal subunit). In this case, the binding affinity is -8.2 kcal/mol. A more negative value indicates a stronger binding interaction (Ali et al. 2021).

The pharmacophore enhanced shape alignment score (PheSA score) is a measure of how well the ligand (Sarecycline) fits within the binding site of the target protein (Cutibacterium acnes 30S ribosomal subunit) based on its shape and pharmacophoric features (Lomakin et al. 2023). A higher score indicates a better fit and compatibility with the binding site (Evbuomwan et al. 2023). Overall, based on the given results, sarecycline demonstrates a strong binding affinity (-8.2 kcal/mol) (Table 1) within the binding site of the Cutibacterium acnes 30S ribosomal subunit. Additionally, it achieves a pharmacophore enhanced shape alignment score of 0.53184 (Table 1), suggesting a good fit and compatibility with the target protein’s binding site.

These results indicate specific interactions between the nucleotides (G1038, C1039, A1183, G1184) of the Cutibacterium acnes 30S ribosomal subunit and sarecycline. The interactions are primarily hydrogen bonds, which involve the formation of weak bonds between the nucleotide and sarecycline. These hydrogen bonds contribute to the stability of the molecular complex. Additionally, there is one hydrophobic interaction between C1039 and sarecycline, where non-polar components of the molecules come into contact (Fig. 1a, b; Table 2).

Figure 1. 

a 2D and b 3D Chemical interactions of Sarecycline within the binding site of the target protein.

Sandaracopimar-15-ene-6.beta.,8.beta.-diol (PUBCHEM ID: 543956) has a binding affinity of -7.3 kcal/mol, although lower than sarecycline (-8.2 kcal/mol).

Sarecycline demonstrates a higher PheSA score (0.53184) compared to Sandaracopimar-15-ene-6. beta.,8. beta. -diol the (0.37252). A higher score suggests a closer structural fit and potentially more favorable ligand-receptor interactions. Therefore, a search for better analogues of Sandaracopimar-15-ene-6. beta.,8. beta. -diol as better alternatives to sarecycline became necessary. Given this, a set of new compounds from Sandaracopimar-15-ene-6. beta.,8. beta. -diol with a de novo design approach using DataWarrior v5.0.0 (Trif et al. 2022) were designed. DataWarrior adopted an evolutionary method that mimics nature by randomly transforming known molecular configurations having small changes to establish novel generations with possibly better structures. Each generation of molecules are tested for robustness with a set of modifiable principles and the most auspicious structures serve as a starting point for subsequent generation. The mutation algorithm executes vicissitudes such as bond order changes, ring aromatisations, replacing an atom, atom insertions, substituent migrations just to mention a few (Hadi et al. 2020).

Every structure to be mutated is firstly evaluated for all possible mutations concerning how extensively the alteration will increase or decrease the drug-likeness. Mutations with alteration in the required direction are assigned a higher probability than mutations that reduce drug-likeness. Mutations that would create high ring tension are eliminated from the list. Based on this approach, 337 structures were created based on sarecycline’s pharmacophores with the corresponding fitness and PheSA scores (Fig. 2).

Figure 2. 

PheSA scores based on sarecycline’s pharmacophores.

Ten compounds across different generation holds higher PheSA score, which makes them a closer structural fit and potentially more favorable ligand in its interactions with Cutibacterium acnes 30S ribosomal subunit when compared to sarecycline (0.53184) (Fig. 3).

Figure 3. 

Ten compounds across different generation having higher PheSA score than sarecycline.

Of these, only compound 1 of the 10^th generation has a binding affinity (-8.3 kcal/mol) slightly higher than sarecycline’s (-8.2 kcal/mol) (Table 3). This interaction is characterized by 5 hydrogen bonds with one hydrophobic interaction (Fig. 4a, b; Table 4).

Figure 4. 

a 2D and b 3D Chemical interactions of compound 1 within the binding site of the target protein.

Furthermore, the absorption, distribution, metabolism and excretion properties of compound 1 and sarecycline were compared based on their physicochemical properties (Table 5), lipophilicities (Table 6), water solubility (Table 7), pharmacokinetics (Table 8) and druglikeness (Table 9). Overall, the results highlight the distinct physicochemical properties of Sarecycline and Compound 1. These properties can impact the compounds’ structural features, flexibility, interaction potentials, and pharmacokinetic profiles, which are crucial considerations in the development of drugs against Acne Vulgaris.

The findings from Fig. 5 provides critical insights into the behavior of Compound 1 during the molecular dynamics’ simulation. During the first 100 nanoseconds of the simulation, Compound 1 exhibited RMSD values ranging from 0.0 to 0.8 Å. These values indicate that the compound maintained a relatively stable conformation with minor fluctuations. This stability is a crucial factor when evaluating its potential as a drug candidate. Compound 1, a novel compound derived from Sandaracopimar-15-ene-6.beta.,8.beta.-diol, with unique structure and design makes it an intriguing candidate for further investigation, particularly for its potential in targeting the Cutibacterium acnes 30S ribosomal subunit as a drug. The statement underscores that Compound 1 is being evaluated as a drug candidate against the Cutibacterium acnes 30S ribosomal subunit. This bacterial ribosomal subunit is a vital target for inhibiting bacterial growth, especially in the context of Acne Vulgaris treatment.

Figure 5. 

Behavior of Compound 1 in Molecular Dynamics Simulation. The plot shows RMSD (Root Mean Square Deviation) and rGyr (Radius of Gyration) against 100 ns window. These metrics provide insights into the stability and structural changes of Compound 1 during the simulation, making it a valuable tool for understanding its behavior in the context of potential drug development.

In the context of discovering drugs against Acne Vulgaris, the physicochemical properties of Sarecycline and Compound 1 are important factors to consider. Molecular weight represents the sum of the atomic weights of all atoms in a molecule (Karthikeyan et al. 2017). In this case, Sarecycline has a higher molecular weight than Compound 1. A higher molecular weight can sometimes indicate larger and more complex molecules. However, it’s important to note that molecular weight alone does not provide information about a compound’s effectiveness or potency for acne treatment. Aromatic heavy atoms represent non-hydrogen atoms in aromatic rings. Sarecycline contains six aromatic heavy atoms, while Compound 1 does not have any. Aromatic rings are common features in many drugs and can contribute to their pharmacological properties (Stumpfe and Bajorath 2011). The presence of aromatic heavy atoms in Sarecycline suggests it may possess aromatic ring systems, potentially influencing its biological activity. The Fraction Csp3 measures the proportion of sp3-hybridized carbon atoms in a molecule (Osguthorpe et al. 2012). A higher Fraction Csp3 indicates a higher proportion of saturated carbon atoms (sp3 hybridized) in the compound’s structure (Sheth and Sheth 2000). Compound 1 has a higher Fraction Csp3, suggesting it contains more saturated carbon atoms compared to Sarecycline. The level of saturation can affect the compound’s lipophilicity, solubility, and other physicochemical properties, potentially influencing its pharmacokinetic profile (Nantasenamat et al. 2009). Rotatable bonds represent single bonds that can rotate freely. The number of rotatable bonds indicates the flexibility of a molecule. Sarecycline has one more rotatable bond than Compound 1 in this instance. A molecule’s interaction with biological targets, such as the enzymes or receptors involved in Acne Vulgaris, may be affected by its degree of flexibility. Atoms that can receive hydrogen bonds are known as H-bond acceptors (Liu et al. 2017). These connections may be extremely important to how a medicine interacts with its target. Sarecycline has more H-bond acceptors than Compound 1, which may indicate that it has a higher propensity for establishing hydrogen bonds, which may alter its affinity for binding to the target proteins used in the treatment of acne.

The absorption, distribution, and effectiveness of a chemical are significantly influenced by its lipophilicity (Lipinski 2004). The term “lipophilicity” describes a substance’s capacity to dissolve in lipids or other compounds that resemble fat. A measurement of a compound’s lipophilicity based on its molecular structure is called iLOGP (intrinsic log P) (Ghose and Crippen 1987). Positive iLOGP readings for both Sarecycline and Compound 1 show some lipophilicity. Sarecycline, however, exhibits a somewhat higher iLOGP value than Compound 1, indicating that it could be marginally more lipophilic. Another indicator of lipophilicity that considers a compound’s molecular makeup and three-dimensional features is called XLOGP3 (Ghose and Crippen 1987). Sarecycline has a positive XLOGP3 value, indicating some lipophilicity. In contrast, Compound 1 has a negative XLOGP3 value, suggesting it is less lipophilic and may be more hydrophilic or polar in nature. WLOGP (water/octanol log P) represents the partition coefficient between water and octanol, which is commonly used as a measure of lipophilicity (Ghose et al. 1999). In this case, Sarecycline has a negative WLOGP value, indicating it is more hydrophilic or water-soluble. Compound 1, on the other hand, has a positive WLOGP value, suggesting it is more lipophilic or soluble in organic solvents. MLOGP (modified log P) is a calculation method that estimates the log P value based on the molecular structure of a compound (Sanderson and Earnshaw 1991). Sarecycline has a negative MLOGP value, indicating higher hydrophilicity, while Compound 1 has a positive MLOGP value, suggesting it is more lipophilic. Silicos-IT Log P is a prediction of the logarithm of the partition coefficient between octanol and water (Tetko et al. 2001). Sarecycline has a negative Silicos-IT Log P value, suggesting it has more affinity for water than octanol, indicating higher hydrophilicity. Compound 1, with a positive Silicos-IT Log P value, exhibits more affinity for octanol, indicating higher lipophilicity. Consensus Log P is an average of multiple log P prediction methods, providing a consensus value for the compound’s lipophilicity (Veber et al. 2002). Both Sarecycline and Compound 1 have positive Consensus Log P values, indicating some degree of lipophilicity. Overall, the lipophilicity results suggest that both Sarecycline and Compound 1 exhibit some degree of lipophilicity, but Compound 1 may have a relatively higher lipophilicity.

Water solubility of a compound is an important factor as it affects its absorption, distribution, and bioavailability. ESOL Log S is a logarithmic measure of water solubility, with negative values indicating poor solubility (Ertl et al. 2000). Both Sarecycline and Compound 1 have negative ESOL Log S values, suggesting low water solubility. Sarecycline has a more negative value, indicating relatively lower water solubility compared to Compound 1. Sarecycline has lower solubility values, indicating poor water solubility. In comparison, Compound 1 has higher solubility values, indicating relatively better water solubility. Sarecycline is classified as soluble, indicating it has some level of solubility in water. Compound 1 is classified as very soluble, suggesting it has a higher level of solubility in water compared to Sarecycline. Ali Log S is another logarithmic measure of water solubility, with negative values indicating poor solubility (Kelder et al. 1999). Both Sarecycline and Compound 1 have negative Ali Log S values, suggesting low water solubility. Sarecycline has a more negative value, indicating relatively lower water solubility compared to Compound 1. Sarecycline has lower solubility values, indicating poor water solubility. Compound 1 has higher solubility values, indicating relatively better water solubility.

In the context of drug discovery against Acne Vulgaris, understanding the pharmacokinetic properties of a compound is crucial to assess its absorption, distribution, metabolism, and excretion. GI absorption refers to the ability of a compound to be absorbed through the gastrointestinal tract (Kerns and Di 2004). Sarecycline is characterized as having low GI absorption, indicating that it may have limited absorption from the gastrointestinal tract into systemic circulation. In contrast, Compound 1 is described as having high GI absorption, suggesting it has a higher potential for absorption from the gastrointestinal tract. Blood-Brain Barrier permeant refers to the ability of a compound to cross the blood-brain barrier (BBB) (Van de Waterbeemd et al. 1998). Both Sarecycline and Compound 1 are not considered BBB permeant, indicating that their capacity to permeate the BBB is somewhat limited. This may be useful in lowering the possibility of adverse consequences involving the central nervous system. A transporter protein called Pgp (P-glycoprotein) is involved in the efflux of substances from cells (Nigam 2015). Compound 1 and Sarecycline are both known as Pgp substrates, proving that P-glycoprotein is responsible for their transport. Their distribution and absorption in different tissues may be affected by this. In general, the pharmacokinetic findings shed light on the distribution, absorption, and possible interactions of compound 1 with sarecycline. These characteristics are crucial factors to take into account when developing new drugs since they might affect the compounds’ tissue distribution, bioavailability, and potential for drug-drug interactions.

Assessing the druglikeness of a compound is crucial to determine its potential as a viable drug candidate (Wetzel et al. 2011). Lipinski’s Rule of Five is a set of guidelines used to assess the druglikeness of a compound based on its physicochemical properties (Lipinski 2004). It defines four criteria related to molecular weight, lipophilicity (log P), hydrogen bond donors, and hydrogen bond acceptors (Ghose and Crippen 1987). A compound is considered to have a Lipinski violation if it fails to meet any of these criteria (Ghose et al. 1999). Both Sarecycline and Compound 1 have one Lipinski violation, suggesting they may have properties that deviate from the optimal range defined by Lipinski’s Rule of Five. Alternatively, Ghose’s Rule is another set of guidelines that assess the druglikeness of a compound based on its physicochemical properties (Veber et al. 2002). Sarecycline has one Ghose violation, indicating a deviation from the optimal range defined by Ghose’s Rule. However, Compound 1 does not have any Ghose violations, suggesting it falls within the favorable range defined by Ghose’s Rule. Also, Veber’s Rule evaluates the druglikeness of a compound based on its rotatable bonds and polar surface area (PSA) (Veber et al. 2002). Compounds that meet the criteria defined by Veber’s Rule are considered more likely to have good oral bioavailability (Barrero et al. 2021). Sarecycline has one Veber violation, indicating it deviates from the optimal range defined by Veber’s Rule. In contrast, Compound 1 does not have any Veber violations, suggesting it falls within the favorable range. In this case, Compound 1 has a higher Bioavailability Score compared to Sarecycline, suggesting that Compound 1 may have relatively better bioavailability.

As mentioned earlier, compound 1 maintained a relatively stable conformation with minor fluctuations. The statement highlights a critical phase in the simulation where Compound 1 became stable, with an RMSD of 0.65 Å observed between 85 to 100 nanoseconds. This stability indicates that the compound’s conformation remained consistent and underwent minimal structural changes during this phase. The observed stability phase suggests that Compound 1 may have established favorable interactions with the Cutibacterium acnes 30S ribosomal subunit drug target. A stable conformation often corresponds to an energetically favorable binding mode, which is encouraging for its role as a drug candidate (Jakhmola et al. 2021).

The measured rGyr values over 100 ns, which gradually climbed to 3.9, 4.0, 4.1, and 4.2, indicate that Compound 1 showed structural flexibility. This adaptability is helpful because it enables the chemical to modify its conformation to interact with the target in a useful way (Lee et al. 2019). Successful drug binding requires the capacity to investigate many structural conformations (Bera and Payghan 2019).

A thorough analysis of Compound 1’s behavior is provided by the combination of RMSD and rGyr data. rGyr values provide information on changes in the compound’s overall size and shape, whereas RMSD reveals stability and fluctuations in its conformation. These measurements provide a complete description of the structural dynamics of Compound 1.

The results of this study show that Sandracopimar compounds and derivatives possess comparable activity and physicochemical parameters with Sarecycline in the management of acne and may thus serve as a potential source of novel anti-acne therapies.