Computational repurposing of Trimethoprim: molecular docking and molecular dynamics simulation studies suggest a potential inhibition of colchicine-binding site.

doi:10.21203/rs.3.rs-3515239/v1

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Computational repurposing of Trimethoprim: molecular docking and molecular dynamics simulation studies suggest a potential inhibition of colchicine-binding site.

https://doi.org/10.21203/rs.3.rs-3515239/v1

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Cancer is a major global health concern, and its incidence is projected to rise in the coming years. Drug repurposing, the identification of new uses for existing drugs, offers a promising approach to accelerating the development of potent and less toxic anti-cancer agents. This in silico study explored the possible repurposing of trimethoprim, an approved synthetic antimicrobial, as a colchicine-binding site (CBS) inhibitor using molecular docking and molecular dynamics (MD) simulations. Trimethoprim shares structural similarities and pharmacophoric features with colchicine and the combretastatins, potent antimitotic agents that target the CBS. The docking results showed that trimethoprim achieved a good binding affinity to the CBS, with an average CDOCKER_ENERGY of -33.75 kcal/mol. The MD simulations (100 nanoseconds) confirmed the stability of the trimethoprim-tubulin complex, with a root mean square deviation (RMSD) of less than 2.5 Å for the protein backbone. The root mean square fluctuation (RMSF) of the binding site residues increased, indicating their increased flexibility. The radius of gyration (Rg) also increased within acceptable limits, suggesting that the protein unfolds to accommodate trimethoprim binding. The binding energy calculated using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach was − 27.3 kcal/mol, which further confirms the docking results. Overall, the findings of this study provide preliminary evidence that trimethoprim has the potential to be repurposed as a CBS inhibitor. Further in vitro and in vivo studies are needed to validate its efficacy and safety as a potential anti-cancer agent.

Anti-cancer

Drug repurposing

Tubulin

Colchicine-binding site

Combretastatin

Trimethoprim

Molecular docking

Molecular dynamics

From discovery to approval, the de novo development of anti-cancer drugs is a costly and lengthy process. According to reported studies, it takes an average of 7.3 years and about $648.0 million to bring a new anti-cancer medicine to market (1). Given the fact that cancer is a leading cause of death worldwide and the number of cancer cases is expected to continue rising in the coming decades, overcoming the challenges of cost and time is becoming a global priority (2).

Drug repurposing, which is a strategy for identifying novel applications of already existing drugs beyond their intended use, can accelerate the discovery of effective and less toxic anti-cancer agents (3). Due to the recent technological advances and the exponential growth of the data of pharmacological compounds, a new era of drug repurposing called computational drug repurposing has emerged (4). Nowadays, repurposed drugs represent 30% of the newly marketed drugs in the United States (5). Successful examples of repurposed drugs include methotrexate for the treatment of rheumatoid arthritis and sildenafil for the treatment of erectile dysfunction (4, 5).

Microtubules are the major component of the eukaryotic cytoskeleton. They are dynamic proteins that play a crucial role in mitosis, cellular transport, and maintenance of cell structure (6). Each microtubule is an assembly of α and β tubulin heterodimers, where the colchicine-binding site (CBS) is located at the interface between α and β subunits (7). Overexpression of class III β-tubulin is a common feature of human tumors and has been linked to increased tumor aggressiveness and poor patient prognosis (8). In addition, microtubules are involved in the metastatic spread of tumor cells, making them a vital target for antimitotic agents (7, 8). Antimitotic agents binding to the colchicine-binding site cause a steric clash and disassembly of the α and β heterodimer leading to tubulin depolymerization (9).

Although colchicine effectively destabilizes microtubules by inhibiting tubulin polymerization, it is not clinically approved as an anti-cancer agent due to its narrow therapeutic index and toxicity to non-cancerous cells (10). The combretastatins are a class of natural diarylstilbenoid structurally related to colchicine. The antiproliferative activity of combretastatins was credited to the combretastatinA series of compounds. Two cis-stilbene compounds from the 17 isolated natural combretastatins have gained significant interest over the years: combretastatin A-1 and combretastatin A-4 (CA-1 and CA-4) (11). Combretastatin A-4 is a potent antimitotic agent that inhibits tubulin polymerization; it binds in a similar orientation as colchicine at the colchicine-binding site. A significant number of CA-4 analogues have been synthesized and characterized, making CA-4 a promising lead compound for the design of colchicine-binding site inhibitors (CBSIs) (12).

Trimethoprim is an approved synthetic antimicrobial drug that inhibits the bacterial dihydrofolate reductase (DHFR) enzyme and subsequently inhibits bacterial DNA synthesis. It has much weaker activity on human DHFR, making it a potent and selective antibacterial agent (13). It is administered in combination with sulfamethoxazole as co-trimoxazole to treat a wide range of gram-positive and gram-negative bacterial infections. Trimethoprim is generally well-tolerated at the dosages used, and studies comparing trimethoprim to co-trimoxazole have shown that skin rashes and gastrointestinal upset are less common when trimethoprim is used alone. (14)

An in vitro study revealed that trimethoprim and its conjugates exert a cytotoxic effect on cancer cells and induce cancer cell apoptosis (15). Furthermore, the trimethoprim structure exhibits structural similarity and common pharmacophoric features with colchicine and the combretastatins (Fig. 1). Prompted by these observations, this in silico study utilizes molecular docking and molecular dynamics techniques to investigate the potential repurposing of trimethoprim as a colchicine binding site inhibitor.

Molecular docking has been an essential tool in computer-aided drug design (CADD) in recent years. It has the potential to significantly improve the efficiency and reduce the cost of drug discovery by predicting binding affinity and analyzing the interactive mode between drug candidates and target proteins. Despite its limitations in modeling the flexibility of proteins and ligands, molecular docking provides the initial coordinates required for molecular dynamics (MD) simulations (16).

Molecular dynamics (MD) simulations are an advanced computational tool used to study the interactions in protein-protein and protein-ligand systems on an atomic level. MD simulations typically generate a trajectory file that records all the dynamic events occurring in a system within a specific period of time (17). The powerful tool, Molecular Mechanics Poisson-Boltzmann Surface (MM-PBSA), is used in the final steps to accurately calculate binding free energies with relatively low computational cost (18). It is recommended to perform molecular dynamics (MD) simulations prior to wet-lab experiments, as they can provide valuable insights into the expected experimental results, such as the conformational changes induced by protein-ligand interactions (19).

By analyzing the data obtained from these modeling techniques, the results of this study could provide a promising lead compound for the development of novel and effective CBSI for the treatment of cancer.

Molecular docking

BIOVIA Discovery Studio software, version 2.5 (https://www.3ds.com/products-services/biovia), was used for all aspects of the molecular docking study, from preparing the ligand and receptor to performing the docking itself. X-ray crystal structures of the apo form of tubulin (PDB ID: 5XP3) and tubulin co-crystallized with combretastatin A-4 (PDB ID: 5LYJ) were both retrieved from the Protein Data Bank (https://www.rcsb.org/). The trimethoprim 3D structure was obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/compound/5578).

First, the apo and the co-crystallized proteins were prepared using the ‘prepare protein’ protocol so that water is removed, while hydrogens and missing loops are added. The definition of binding site was based on the co-crystallized CA-4 with a radius of 8 Å. Then, the ligands (the co-crystallized CA-4 and trimethoprim) were prepared using the ‘prepare ligands’ protocol, with isomers and tautomers excluded. Finally, the ligands were docked into the defined colchicine-binding site of tubulin (PDB ID: 5LYJ) using the CDOCKER protocol to obtain the CDOCKER_ENERGY and CDOCKER_INTERACTION_ENERGY. Discovery Studio Visualizer 21.1.0 was employed to analyze the protein-ligand interactions in 2D and 3D.

The docking study was validated by redocking the co-crystallized CA-4 into the colchicine-binding site using the same protocol. The top-score pose was superimposed on the native ligand pose to calculate the root mean square deviation (RMSD), where a low value of RMSD was obtained (0.72 Å) as shown in Fig. 2. This indicates that the docking protocol is valid and can predict the binding modes of trimethoprim to the colchicine-binding site.

Molecular dynamics simulation

To compare the dynamics of the tubulin protein in its apo form and in complex with trimethoprim, 100-ns molecular dynamics simulations were performed for each of them using GROMACS 2020.3 software (https://www.gromacs.org/ ).

Protein topology files were generated, from the PDB files obtained from docking, with the AMBER99SB force field (20). The ligand topology of trimethoprim was created utilizing the Acpype tool to match the chosen forcefield (21). The complex was solvated in a triclinic box type containing TIP3P (Transferable Intermolecular Potential 3-Point), where 14900 water molecules and 7 Na + ions were added to neutralize the system (22). The energy was then minimized using the steepest descent minimization algorithm to a maximum of 50000 steps.

Consequently, equilibration was performed with the help of canonical (NVT) and isothermal-isobaric (NPT) ensembles by applying the Leap-Frog method for integration up to 50,000 steps (23). The temperature of the system was maintained at 300 K by applying the modified Berendsen thermostat, while the pressure was preserved at 1 bar with the Parrinello-Rahman pressure coupling method. The particle mesh Ewald (PME) method was used to calculate the electrostatic interactions, using a cutoff of 1.0 nm for both electrostatic and Van der Waals forces (24). Eventually, the equilibrated system underwent a 100 ns simulation run with a timestep of 2 femtoseconds. The resulting trajectory was analyzed to obtain the following plots: RMSD, RMSF, radius of gyration, and H-bond analysis.

The Molecular Mechanics/Poisson–Boltzmann Surface Area (MM‑PBSA)

The molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) approach, a binding energy calculation method that is both efficient and reliable (18), was applied to analyze the total binding energy of the trimethoprim-tubulin complex. The enthalpic component of the binding free energy (ΔH), a thermodynamic quantity that can determine the stability of the simulated complex, was calculated using the gmx_mmpbsa module of GROMACS 2020.3 (25, 26). The following simplified equations were applied:

ΔG_binding = ΔH − TΔS.

ΔH = ΔE_{electrostatic} + ΔE_vdW + ΔG_polar + ΔG_nonpolar

Where ΔE electrostatic, ΔE vdW, ΔG polar, and ΔG non-polar represent the electrostatic contribution, the Vander Waals contribution, and polar and nonpolar solvation terms, respectively. The non-polar solvation term is more commonly known as the SASA (solvent accessible surface area) contribution. (26)

The colchicine binding site, first identified in 2004 by Ravelli et al., is located at the interface between α and β subunits with a pocket size of 4–5 Å. The volume of the CBS site is determined by the spatial arrangement of helix 7 (H7), loop 7 (T7), and helix 8 (H8). Structural interaction fingerprinting (SIFt) analysis of seven reported tubulin crystal structures revealed three distinct interaction zones on the CBS domain. The main zone (zone 2), located on the β-subunit, comprises 13 amino acids and accommodates the largest part of the ligand's structure. The other two zones are complementary; zone 1 lies at the α-subunit interface and comprises 5 amino acids, while zone 3 is buried deeper within the β-subunit and consists of 8 amino acids. To sum up, inhibitors bind mainly to the β-tubulin subunit leading to loss of lateral contact between α- and β-subunits and subsequent depolymerization of tubulin (9, 27).

A study by Nguyen et al. identified seven important pharmacophoric features of the CBS inhibitors: three H-bond acceptors (A1, A2, and A3), one H-bond donor (D1), two hydrophobic nuclei (H1 and H2), and one planar group (R1). It was established that the minimum pharmacophoric features crucial for activity are one hydrogen bond acceptor, two hydrophobic centers, and a planar group (Fig. 3). (28)

The trimethoxyphenyl moiety of colchicine and combretastatins (A1 and A4) is of proven importance in the structure-activity relationship of CBSIs. An investigation into the effect of altering this essential portion revealed that modifications did not enhance the antiproliferative activity, and proved that preserving at least one methoxy group was essential (7). The trimethoprim structure consists of a trimethoxyphenyl moiety connected to a pyrimidine ring, and it successfully matches six of the seven important pharmacophoric features of the CBS (Fig. 4).

Molecular docking

Since the major part of the CBS is located deep into the β-tubulin subunit, molecular docking was performed on the β-tubulin subunit. According to the results of the CDOCKER protocol, trimethoprim conformers achieved a lower and better average CDOCKER_ENERGY score (-33.75 kcal/mol) than combretastatin A-4 conformers (-22.05 kcal/mol). Furthermore, the average value of CDOCKER_INTERACTION_ENERGY for trimethoprim conformers (-41.2 kcal/mol) was comparable to combretastatin A-4 conformers (-43.9 kcal/mol).

The 2D interaction diagram (Fig. 5) revealed that trimethoprim formed interactions in all three zones of the CBS. In the main zone (zone 2), the trimethoxyphenyl moiety formed an essential hydrogen bond with Cysβ241, and two carbon-hydrogen bonds with Alaβ317 and Lysβ352. Alkyl/Pi-Alkyl interactions in zone 2 involved Ileβ378, Alaβ316, Leuβ248, Alaβ250, and Leuβ255. In addition, trimethoprim formed a single carbon-hydrogen bond with Valβ238 in zone 3 and a single pi-sulfur interaction with Metβ259 in zone 1. Both the docking score and the binding mode of trimethoprim suggest a good fitting and potential activity as a CBS inhibitor.

Molecular dynamics simulations

Molecular dynamics simulations are an essential tool for observing protein-ligand interactions at an atomic level and gaining insights into their dynamics (19). For the initial structure, the best conformer of trimethoprim was selected not only on the basis of the CDOCKER_ENERGY score, but also on its interactions with the CBS. The MD simulations of the apo form of β-tubulin and the trimethoprim-β tubulin complex were performed for a time period of 100 ns.

The root mean square deviation (RMSD) plot was used to assess the conformational stability of the protein-ligand complex; the lower the RMSD value, the more stable the complex. The trimethoprim-β tubulin complex showed an average RMSD value less than 0.25 nm (2.5 Å), which confirms the optimal fitting of trimethoprim in the binding site and indicates its stability throughout the simulation period. However, it showed a higher average RMSD than the apo form of β-tubulin, which indicates conformational changes in the protein upon complex formation (Fig. 6).

The root mean square fluctuation (RMSF) plot was generated, for both the ligand-free and the ligand-bound forms of protein, to estimate the effect of trimethoprim binding on the β-tubulin subunit’s flexibility (Fig. 7). Protein residues with higher RMSF values are more flexible and have a greater potential to interact with ligand molecules. Apart from the N-terminal and C-terminal residues, the highest spikes are observed at residues no. from 250 to 350, which represent the main zone of the active site (zone 2). The increased flexibility in the active site upon trimethoprim binding indicates the increased interaction potential and confirms the adaptation of trimethoprim in the CBS.

According to previous conformational studies, the superposition of the apo form of tubulin and the tubulin-inhibitor complex reveals a significant structural change in the CBS. The T7 loop, which spans from Alaβ250 to Pheβ244, gets displaced leading to the opening of the colchicine-binding pocket (27). To assess the impact of trimethoprim binding on protein compactness and folding, the radius of gyration (Rg) was calculated and plotted. While a small Rg value indicates more compactness, the results revealed that trimethoprim binding increased the radius of gyration which confirms the unfolding of protein and opening of the CBS. However, the overall average value of Rg was less than 2.5 nm (25 Å) over the simulation period, which reflects the overall system stability (Fig. 8).

Hydrogen bond analysis

Hydrogen bonds play a fundamental role in stabilizing the ligand-protein complex. The number and strength of hydrogen bonds between the ligand and the protein can have a significant impact on the binding affinity of the ligand-protein complex (29). Throughout the simulation, trimethoprim formed an average of 3 H-bonds within the CBS with a maximum of 7 H-bonds and a minimum of 0 H-bonds. As the simulation progressed, the average number of hydrogen bonds decreased. However, at least one hydrogen bond was stable until the end of the simulation period (Fig. 9).

The Molecular Mechanics/Poisson–Boltzmann Surface Area (MM‑PBSA)

MM-PBSA calculations were applied to measure the enthalpic component of the binding free energy. As shown in Table 1, the contribution of Van der Waals, electrostatic, and SASA energy to the overall total energy was negative, while the positive contribution was represented by polar solvation energy. Van der Waals energy was observed to be the primary contributor to the interaction between trimethoprim and the β-tubulin subunit with − 37.48 kcal/mol. The more negative the enthalpy value, the more favorable the protein-ligand interaction. Hence, the total binding energy of -27.3 kcal/mol confirms the favorable binding of trimethoprim to the CBS.

Table 1

MM-PBSA calculations of total binding energy and its constituent energies for trimethoprim-tubulin complex.
Complex	Total Binding Energy (kcal/mol)	Van der Waals Energy (kcal/mol)	Electrostatic Energy (kcal/mol)	Polar Solvation Energy (kcal/mol)	SASA Energy (kcal/mol)
Trimethoprim-Tubulin	-27.30	-37.48	-13.04	28.37	-5.16

This in-silico study investigated the potential repurposing of trimethoprim, an approved synthetic antimicrobial, as a tubulin polymerization inhibitor by modeling its binding to the colchicine-binding site (CBS) using molecular docking and molecular dynamics (MD) simulations.

The docking results revealed that trimethoprim exhibited a good binding affinity to the CBS with an average CDOCKER_ENERGY of -33.75 kcal/mol. The MD simulations confirmed the stability of the trimethoprim-tubulin complex, with an RMSD less than 0.25 nm (2.5 A) for the protein backbone. The RMSF of the binding site residues increased, indicating increased flexibility. The radius of gyration (Rg) also increased, indicating that the protein unfolds to bind to trimethoprim. The binding energy calculated using the MMPBSA approach was − 27.3 kcal/mol, which is in good agreement with the docking results.

Finally, the results of this study suggest that trimethoprim has the potential to be repurposed as a tubulin polymerization inhibitor. Further in vitro and in vivo studies will be conducted to validate its efficacy as a potential anti-cancer agent.

CBS

Colchicine-binding site

CA-1

Combretastatin A-1

CA-4

Combretastatin A-4

CBSIs

colchicine-binding site inhibitors

DHFR

dihydrofolatereductase

CADD

Computer-aided drug design

Molecular dynamics

MM-PBSA

Molecular Mechanics/Poisson–Boltzmann Surface Area

RMSD

Root Mean Square Deviation

TIP3P

Transferable Intermolecular Potential 3-Point

NPT

Number of atoms, Pressure, Temperature

NVT

Number of atoms, Volume, Temperature

PME

Particle mesh Ewald

SIFt

Structural interaction fingerprint

SASA

solvent accessible surface area

RMSF

Root mean square deviation

Radius of gyration

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

No Funding was available for the project.

Authors' contributions

KA designed the current study. SO did the computational modeling work. MI analyzed the data obtained. EZ prepared the figures. This paper was written, revised, and approved by all authors.

Acknowledgements

Not applicable

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No competing interests reported.

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Computational repurposing of Trimethoprim: molecular docking and molecular dynamics simulation studies suggest a potential inhibition of colchicine-binding site.

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Abstract

Figures

Introduction

Materials and method

Molecular docking

Molecular dynamics simulation

The Molecular Mechanics/Poisson–Boltzmann Surface Area (MM‑PBSA)

Results and discussion

Molecular docking

Molecular dynamics simulations

Hydrogen bond analysis

The Molecular Mechanics/Poisson–Boltzmann Surface Area (MM‑PBSA)

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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