Exploring DNA Binding of Benzothiazole-based Known Drugs: A Molecular Docking Investigation
Uzma Khan1, Souvik Sur2*
1Department of Chemistry, Faculty of Engineering, Teerthanker Mahaveer University,
Moradabad, Uttar Pradesh - 244001, India.
2Research and Development Center, Teerthanker Mahaveer University,
Moradabad, Uttar Pradesh - 244001, India.
*Corresponding Author E-mail: drsouvik.engineering@tmu.ac.in
ABSTRACT:
Lubeluzole (Prosynap) operates as an indirect NMDA antagonist by inhibiting glutamate release, blocking nitric oxide production, and modulating calcium- and sodium-gated ion channels.
Initially developed for stroke treatment, it exhibits neuroprotective properties, particularly in hypoxic conditions.4 Pramipexole, marketed under brand names like Mirapex, is employed in the treatment of Parkinson's disease and restless legs syndrome. It can be used alone or in combination with levodopa for Parkinson's disease management. Pramipexole falls into the non-ergoline class of dopamine agonists. Probenazole, a member of the 1,2-benzothiazole class, features a substitution at position 3 with an allyloxy group.5 This agrochemical antifungal and plant activator is primarily used to combat rice blast.6 Riluzole is recommended for patients with amyotrophic lateral sclerosis, as it prolongs life expectancy and delays the need for tracheostomy. It also demonstrates neuroprotective effects in various in vivo experimental models of brain damage, including excitotoxic pathways.7 Viozan, a novel dual D2 dopamine receptor and beta2-adrenoceptor agonist, is under investigation for its potential to alleviate symptoms associated with chronic obstructive pulmonary disease (COPD).8 Zopolrestat, an effective aldose reductase (AR) inhibitor with an IC50 of 3.1 nM, is used in research related to diabetes complications.9 We have chosen eight marketed drugs (Bentaluron, Ethoxzolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Zopolrestat and Viozan) here to study whether those can be used in oligonucleotide therapy or not.
Since the oligonucleotide recognitions of the drugs can be an interesting finding. Hurley (2002) reported in literature that many anticancer drugs target DNA.10 Antitumour antibiotics tend to be more specific in their interactions with DNA. Since no previous study was reported with the DNA recognition of Bentaluron, Ethoxzolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Zopolrestat and Viozan (Figure 1), we have eager to know the possibilities of those drugs with DNA. Hoechst and other minor groove ligands specifically bind to AT/GC specific sequences (Pjura et al, 1987, Harshman et al, 1985 and Singh et al, 1992),11-13 where Hoechst is basically benzimidazole based molecule (Singh et al, 2013).14 The hexadecamers d(GCGCGCGCGCGCGCGC)2 and d(ATATATATATATAT)2 sequences are very prone to find whether the chosen drugs effectively bind to DNA strands or not. In the same context, we have aerlier reported various benzimidazole based drugs bound to these DNA sequences differentially.15 Therefore, systematic studies by designing analogues with improved sequence selectivity would facilitate a comprehensive understanding of drug–DNA interaction leading to the development of better drug designing. In the present study, we have compared the sequence recognition properties of Bentaluron, Ethoxzolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Zopolrestat, Viozan which is basically based on Benzothiazole moiety by means molecular docking approach. We also compare their binding scenario towards two completely different synthetic oligonucleotides. The findings from our study can open a window for drug repurposing purposes.
Figure 1: Chemical structures of (a)Bentaluron, (b) Ethoxzolamide, (c) Lubeluzole, (d) Pramipexole, (e) Probenzole, (f) Riluzole, (g) Zopolrestat, (h) Viozan.
MATERIAL AND METHODS:
We used AutoDock, a highly regarded non-commercial docking programme,16,17 for our molecular docking experiment with the drugs Bentaluron, Ethoxazolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Viozan, and Zopolrestat with the hexadecamers d(GCGCGCGCGCGCGCGC)2 and d(ATATATATATATAT)2 sequences. To further improve the thermodynamic stability of the ligand linked to the DNA duplexes, we used a stochastic Lamarckian evolutionary algorithm for docking approach while concurrently minimizing its scoring function. We docked the following medications using AutoDock Vina 4.2: Bentaluron, Ethoxazolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Viozan, and Zopolrestat. The Graphical User Interface programme AutoDock Tools (ADT) was used to perform intermediary tasks, such as creating grid boxes and pdbqt files for DNA and ligand preparation. We have manually added the polar hydrogens, Kollman charges to the targeted DNA sequences. The initial files of targeted DNA and drugs were saved in PDBQT format. AutoGrid was used for the preparation of the grid map using a grid boxwas and the dimensions were set to 50 × 50 × 50 xyz points with a spacing of 0.275 Ĺ. The docking had been done in the grid box constituting minor and major groove of DNA so that we can compare whether the drugs bind to major or minor groove. The docked structures that were acquired were examined using Biovia Discovery Studio (Jejurikar et al., 2021; Biovia, 2017).18,19 The labelled nucleotides, also known as the interacting residues, were in intimate contact with all three analogues. The presence of any potential interactions, such as H-bonding or other potential van der Waal interactions, in each docked complex was examined.
RESULT AND DISCUSSION:
We have performed all the experiments using two target designed DNA sequences: d(ATATATATATATATAT)2 and d(GCGCGCGCGCGCGCGC)2. The molecular docking scores obtained from the most effective poses are tabulated in Table 1.
Table 1: Docking Scores calculated
|
Ligand |
Docking score with d(ATATATATATATATAT)2 |
Docking score with d(GCGCGCGCGCGCGCGC)2 |
|
Bentaluron |
-6.24 |
-4.29 |
|
Ethoxzolamide |
-4.02 |
-4.28 |
|
Lubeluzole |
-6.47 |
-4.33 |
|
Pramipexole |
-6.15 |
-4.40 |
|
Probenzole |
-4.96 |
-3.44 |
|
Riluzole |
-3.40 |
-2.92 |
|
Zopolrestat |
-5.86 |
-3.60 |
|
Viozan |
-3.35 |
-3.99 |
*Scores were obtained as binding free energies in kcal mol-1
Bentaluron, Ethoxazolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Viozan, and Zopolrestat were found to bind in major groove because of their 3D structures and acceptor site availability in the groove pockets (Figure 2). The interactive residues in this case nucleotides found in case of d(ATATATATATATATAT)2 are in major groove of DNA duplex.
Figure 2: (A) Docked structure of Bentaluron and Zopolrestat with AT-Sequence and GC-Sequence, (B) Docked structure of Bentaluron and Zopolrestat with AT-Sequence and GC-Sequence
On the other hand, all eight medicines were exclusively attached to the main groove of the DNA duplex using the nucleotide sequence d(GCGCGCGCGCGCGCGC)2. Table 2 lists each of the residues that were observed. Their binding circumstances in each DNA-drug complex are reflected by the matching docking scores.
Table 2: Docking pose with interactive residues
|
Ligand |
Docking pose with interactive residues* in d(ATATATATATATATAT)2 |
Docking pose with interactive residues* in d(GCGCGCGCGCGCGCGC)2 |
|
Bentaluron |
Residue: Ade5, Thy27, Thy26, Ade25, Thy24, and Ade23 |
Residue: Gua7, Cyt8, Gua23, Gua22, Cyt21 |
|
Ethoxzolamide |
Residue: Thy22, Ade23, Thy24, Ade9 |
Residue: Cyt6, Gua7, Gua25, Cyt24, Gua23, Gua22, Cyt21, Gua20, Cyt9, Cyt8 |
|
Lubeluzole |
Residue: Thy24, Ade25, Thy26, Thy8, Ade7, Thy6, Ade9, |
Residue: Gua7, Cyt8, Cyt24, Gua23, Gua22, |
|
Pramipexole |
Residue: Thy26, Ade25, Thy24, Ade11, Ade9 |
Residue: Cyt6, Gua 25, Cyt24, Gua23, Gua22, Cyt21, Gua20, Cyt9, Cyt8, Gua7, Cyt6, |
|
Probenzole |
Residue: Thy12, Ade13, Thy10, Ade11, Ade21, Thy22, Ade23 |
Residue: Cyt6, Gua7, Cyt24, Gua23, Gua22 |
|
Riluzole |
Residue: Thy6, Ade5, Ade7, Thy8, Ade23, Thy24, Ade26, Thy26, Ade27, |
Residue: Gua7, Cyt8, Gua23, Gua22, Cyt21 |
|
Zopolrestat |
Residue: Thy24, Ade23, Thy22, Ade26, Thy27, Ade28, Thy6, Ade7, Thy8 , Ade9, Thy10 |
Residue: Cyt6, Gua7, Cyt8, Cyt9, Gua10, Cyt21, Gua22, Gua23, Cyt24, Gua25 |
|
Viozan |
Residue: Thy6, Ade7, Thy8, Ade25, Thy24, Ade23, Thy22. |
Residue: Gua7, Cyt8, Gua22, Cyt24 |
*Ade=Adenine, Thy=Thymine, Gua=Guanine, Cyt=Cytosine
The docked analogues were shown from their best docking complexes. The three-dimensional structures after docking were analyzed and the interactive nucleotide residues were identified. In most of the cases with AT-rich DNA track, the binding of drug moieties came from both side of the DNA strands whereas with GC-track mostly ineffective binding of drugs were observed. The docking score here proportionately increases with the increased number of neighbor nucleotide residues in each case. The types of interactions like van der Waal and pi-pi interactions are also found among the docked structures which were found to be actual reflections of their docking scores.
Docking with AT-rich sequence:
Bentaluron displayed binding interactions with an AT-rich DNA sequence that comprised the nucleotides Ade5, Thy27, Thy26, Ade25, Thy24, and Ade23. Conversely, Ethoxzolamide exhibited binding affinities with Thy22, Ade23, Thy24, and Ade9 within a distinct AT-rich DNA sequence. Lubeluzole demonstrated its docking capability with Thy24, Ade25, Thy26, Thy8, Ade7, Thy6, and Ade9 in an AT-rich DNA context. Pramipexole's interactions were observed with Thy26, Ade25, Thy24, Ade11, and Ade9 within yet another AT-rich DNA sequence.
In another instance, Riluzole engaged with an AT-rich DNA sequence encompassing Thy6, Ade5, Ade7, Thy8, Ade23, Thy24, Ade26, Thy26, and Ade27. Similarly, Zopolrestat was seen to interact with the same AT-rich DNA sequence, including Thy24, Ade23, Thy22, Ade26, Thy27, Ade28, Thy6, Ade7, Thy8, Ade9, and Thy10. Lastly, Viozan exhibited binding interactions with Thy6, Ade7, Thy8, Ade25, Thy24, Ade23, and Thy22 within a separate AT-rich DNA sequence.
Docking with GC-rich sequence:
Bentaluron engaged in docking interactions with a GC-rich sequence comprising residues Gua7, Cyt8, Gua23, Gua22, and Cyt21. Meanwhile, Ethoxzolamide demonstrated docking interactions with a distinct GC-rich sequence encompassing Gua6, Gua7, Gua25, Gua24, Gua23, Gua22, Cyt21, Gua20, Cyt9, and Cyt8. Lubeluzole exhibited docking affinity with a GC-rich sequence involving Gua7, Cyt8, Cyt24, Gua23, and Gua22. Pramipexole's docking interactions were observed with a GC-rich sequence containing Cyt6, Gua25, Cyt24, Gua23, Gua22, Cyt21, Gua20, Cyt9, Cyt8, Gua7, and Cyt6. Riluzole was found to dock with GC-rich sequences that included Gua7, Cyt8, Gua23, Gua22, and Cyt21. On the other hand, Probenzole's docking interactions were with Gua6, Gua7, Cyt24, Gua23, and Gua22 within a GC-rich sequence. Zopolrestat was docked with a GC-rich sequence that contained Cyt6, Gua7, Cyt8, Cyt9, Gua10, Cyt21, Gua22, Gua23, Cyt24, and Gua25. Lastly, Viozan exhibited docking interactions with a GC-rich sequence involving Gua7, Cyt8, Gua22, and Cyt24.
CONCLUSION:
According to the results of the current investigation, Bentaluron, Ethoxazolamide, Lubeluzole, Pramipexole, Probenzole, Riluzole, Viozan, and Zopolrestat bind AT and GC-rich DNA sequences differently. The three-dimensional structures allow them to attach to DNA's minor and major grooves with different preferences. Bentaluron, Lubeluzole, Pramipexole bind more firmly to the d(ATATATATATATATAT)2 sequence than Ethoxazolamide and Riluzole do; this is supported by the docking scores. However, it was found that the medicines were ineffectively bound in the grooves with GC-rich DNA sequence d(GCGCGCGCGCGCGC)2. In the future, more confirmation can be obtained via structural studies using molecular dynamics. The broader context of this research lies in the diverse applications of DNA-targeting drugs, spanning cancer therapy, antiviral drug development, and gene regulation. Repurposing of established drugs with established safety profiles for interactions with DNA sequences may accelerate drug development, offering new treatment possibilities for a range of diseases.
ACKNOWLEDGEMENT:
UK is thankful to Teerthanker Mahaveer University, Moradabad for financial assistance and facility available for her research work. SS is also thankful to the facility provided by Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India and granting seed money for the completion of this project via ref. TMU/R.O./2020-21/Seed money /002 dated 19/06/2021.
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Received on 15.09.2023 Modified on 03.10.2023
Accepted on 18.10.2023 ©AJRC All right reserved
Asian J. Research Chem. 2023; 16(5):383-388.
DOI: 10.52711/0974-4150.2023.00062