|Year : 2021 | Volume
| Issue : 1 | Page : 52-56
Topiramate, as prominent dual inhibitor, targeting beta-secretase and voltage-gated sodium channel: An In silico study for the management of epilepsy-associated alzheimer's disease
Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
|Date of Submission||15-Dec-2020|
|Date of Decision||15-Jan-2021|
|Date of Acceptance||29-Jan-2021|
|Date of Web Publication||31-Jul-2021|
Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha
Source of Support: None, Conflict of Interest: None
Background: Alzheimer's disease (AD) is evidenced by decreased cognitive function and increased prevalence of seizures. The association of epilepsy with AD is of clinical importance. Besides, memory impairment is common in epilepsy patients. Anti-epilepsy drugs have been used in various neurodegenerative disorders other than epilepsy. Objective: To validate the assumption that an AED could be effective against AD. The therapeutic target in the cure of epilepsy is the voltage-gated sodium channel (VGSC), while beta-secretase (BACE) is a vital target in AD treatment. Materials and Methods: In this study, we describe the molecular interactions of topiramate with BACE and VGSC by “Autodock 4.2.” Free binding energy and inhibition constant of “topiramate-BACE” and “topiramate-VSC” interactions were found to be “−5.67 kcal/mol and 69.69 μM;” and “−5.64 kcal/mol and 73.88 μM,” respectively. Results: Both hydrophobic interactions and H-bond exhibit a vital role in the binding of topiramate with the BACE and VGSC. Conclusion: The study suggests that topiramate might act as a prominent dual inhibitor against BACE and VGSC, which may prove to be a promising treatment option for epilepsy-associated AD.
Keywords: Alzheimer's disease, beta-secretase, epilepsy, topiramate, voltage-gated sodium channel
|How to cite this article:|
Abohashrh M. Topiramate, as prominent dual inhibitor, targeting beta-secretase and voltage-gated sodium channel: An In silico study for the management of epilepsy-associated alzheimer's disease. King Khalid Univ J Health Sci 2021;6:52-6
|How to cite this URL:|
Abohashrh M. Topiramate, as prominent dual inhibitor, targeting beta-secretase and voltage-gated sodium channel: An In silico study for the management of epilepsy-associated alzheimer's disease. King Khalid Univ J Health Sci [serial online] 2021 [cited 2022 May 27];6:52-6. Available from: https://www.kkujhs.org/text.asp?2021/6/1/52/322882
| Introduction|| |
Alzheimer's disease (AD) is mostly described by a deterioration in cognitive ability and an enhanced prevalence of seizures. Many investigators have examined seizures in AD patients, and there are different opinions about its possible consequence to the pathophysiology of AD. Seizures are associated with alter synaptic function and are risk factors for epilepsy, autism, schizophrenia, and AD. Several factors are responsible for the development of AD, such as, intracellular hyperphosphorylated tau protein, collection of extracellular Aβ42, and generation of reactive oxygen species due to mitochondrial dysfunction. In the USA, during 2015, the reported cases of AD were over 5.3 million and by 2050, dementia patients worldwide will be predicted up to 131.5 million., AD is the sixth cause of death in the US. The death was recorded as 122,019 from AD in 2018. The total payment was estimated to be $305 billion for the age of 65 years and older with dementia during 2020.
Voltage-gated sodium channels (VGCs) is a potent target in epilepsy management. VGCs are integral membrane proteins and exhibit an important role in action potentials generation and propagation in neurons. The vital contribution of sodium channels in electrogenesis reflects them as a promising target for therapeutic approaches targeting to attenuate the neuronal firing that result in pain. At the resting stage, these channels are inactive (close) but endure structural modification in response to depolarization of the membrane, resulting in channel cycling of open (activated), close, and re-priming states.
Beta-secretase (BACE) is a well-known target in the management of AD. BACE is involved in the cleavage of amyloid precursor protein resulting in AD pathogenesis. In AD patients, enhanced BACE activity damages the neuronal cell leading to neurodegeneration.
Epilepsy and AD are distinct from each other in the medical community; however, seizures appear in some patients with AD. Besides, memory impairment is common in epilepsy patients. Anti-epilepsy drugs (AEDs) have been used in various neurodegenerative disorders (ND) other than epilepsy. These NDs, generally, comprise the ion channels' modulated neuronal excitability, signaling pathways (intracellular), and are the potential targets of the AEDs.
Bakker et al. have recently demonstrated that the association between epilepsy and AD is greater than previously thought. In the early stages of AD, various experimental data using AD mouse models indicated that seizures could substantially lead to the progression of AD symptoms, i.e., cognitive dysfunction. Researchers in the USA have described novel roles of AEDs for the treatment of neurodegenerative diseases such as AD and Parkinson's disease. The beneficial effect on neurons was detected by T-type calcium channel blockers (AEDs). The longevity of neurons relies primarily on the brain's calcium signaling pathways. It has been shown that calcium homeostasis is disrupted with age in the brain, which can contribute to cognitive and functional deterioration. This increases the ability of chemicals to modulate calcium homeostasis and protect neurons.
Topiramate is a sulfamate-substituted monosaccharide and employed as an antiepileptic (anticonvulsant) drug (AED). Topiramate widens the blood vessels in the brain which become constrained by enhanced levels of serotonin and is employed as a cure for a typical migraine sufferer., To validate the assumption that an AED could be effective against AD, we performed a state of the art in silico techniques to check the inhibitory potential of topiramate against AD.
| Methodology|| |
Protein and ligand preparation
The three-dimensional (3D) structure of BACE (PDB ID: 1W51), VGSC (PDB ID: 2KAV), and carbonic anhydrase (CA) II (PDB ID: 3HKU) was obtained from Protein Data Bank. Topiramate (CID: 5284627) was obtained from the “PubChem” database.
Topiramate was docked with the BACE, VGSC, and CA II using the “Autodock4.2” tool as described elsewhere. X, Y, and Z coordinates used were 73.794, 54.270, and 11.511 for BACE; −9.55, 0.189, and 5.121 for VGSC; and 11.498, −0.001, and 11.104 for CA II, respectively. The Lamarckian genetic algorithm was employed to perform the docking simulation. The Discovery Studio Visualizer was used to prepare the final figures.
The best “topiramate-BACE” and “topiramate-VGSC” complexes were analyzed for Ligplot analysis for the determination of H-bond and hydrophobic interaction between the topiramate and target proteins (BACE and VGSC).
The drug-likeness, pharmacokinetics, and medicinal chemistry properties of the ligand molecule were checked by SwissADME.
| Results|| |
In physicochemical properties and toxicity assessment, topiramate was found to be safe for use and showing lead-likeness property, as shown in [Figure 1]. The structure of BACE, VGSC, CA II, and topiramate is shown in [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, respectively. In this study, the molecular interaction of topiramate with BACE and VGSC was explored to get insight into its anti-Alzheimer's as well as the antiepileptic effect. Topiramate was observed to bind with BACE through different amino acid residues, namely Gly11, Gln12, Gly13, Asp32, Tyr71, Gln73, Lys107, Phe108, Ile110, Ile118, Gly230, Thr232, and Thr231 [Figure 2]e. Binding energy (△G) and inhibition constant (Ki) for the “topiramate-BACE interaction” were found to be −5.67 kcal/mol and 69.69 μM, respectively [Table 1]. Topiramate was found to make H-bond with Gly230 and Thr232 residues of BACE, while Gly11, Gln12, Gly13, Asp32, Thy71, Gln73, Lys107, Phe108, Ile118, and Thr231 were the hydrophobic interacting residues of BACE with topiramate [Figure 2]f.
|Table 1: Binding energy and inhibition constant values of topiramate with Beta - secretase and voltage - gated sodium channel|
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|Figure 2: Molecular interaction of the selected ligand with targets. (a) Three-dimensional structure of beta-secretase, (b). Three-dimensional structure of VGSC, (c). Three-dimensional structure of CA II, (d) Structure of the ligand Topiramate, (e and f) Three dimensional and two-dimensional structures of the complex "beta-secretase-Topiramate," (g and h) Three-dimensional and two-dimensional structures of the complex "VGSC-Topiramate," (i and j) Three-dimensional and two-dimensional structures of the complex "CA II-Topiramate"|
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Topiramate was observed to bind with VGSC through different amino acid residues, namely Glu1788, Leu1790, Phe1795, Thr1862, and Leu1866 [Figure 2g]. △G and Ki values for the “topiramate-VGSC interaction” were observed to be −5.64 kcal/mol and 73.88 μM, respectively. Amino acid residue Glu1788 of VGSC was found to make H-bond with topiramate, while Leu1866, Thr1862, Leu1790, and Phe1795 were involved in the hydrophobic interaction with topiramate [Figure 2h].
Further, amino acid residues Gln157, Glu220, Gln221, and Lys224 of CA II were found to interact with topiramate [Figure 2i and j]. △G and Ki values for the “topiramate-CA II interaction” were observed to be −5.98 kcal/mol and 29.67 μM, respectively [Table 1].
| Discussion|| |
The AD-related epileptic disorder requires greater consideration because it has a negative effect on these individuals, can quickly go unrecognized and untreated, and can indicate pathogenic mechanisms that can lead to other aspects of the condition. The association of epileptic activity with AD has curative inferences because the epileptic activity can arise at the early stages of the disease and might contribute to pathogenesis.
The use of AEDs in various neurological disorders other than epilepsy has been documented which comprise the neuronal excitability via the ion channels' modulation, receptors, and intracellular signaling pathways and are the targets of the AEDs. Management of clinical seizures in AD patients with selected AEDs, in small doses, is efficient and well tolerated. Topiramate is an AED, originally intended as an oral hypoglycaemic, an anticonvulsant was subsequently authorized. The use of amygdala-kindled seizures in animal models and the elevated prevalence of comorbid psychological symptoms in epilepsy is based on the putative mutual biological cause between epilepsy and bipolar disorders proposed in bipolar spectrum disorders.
Absorption, distribution, metabolism, and excretion of the selected drug topiramate were checked by SwissADME, and were found to possess the good drug-likeness property, which helps in the drug discovery process. Gly11, Gln12, Gly13, Asp32, Tyr71, Gln73, Lys107, Phe108, Ile110, Ile118, Gly230, Thr232, and Thr231 residues of BACE were important in interaction with the topiramate. It is consistent with other studies in which the amino acid residues Leu30, Tyr71, Gln73, Lys107, Phe108, Ile110, Trp115, Ile118, Gly230, and Thr231 of BACE exhibit an important role in the substrate binding.
Ligplot analysis assists in the identification of H-bond and hydrophobic interaction between the “ligand-target” complex. Topiramate was found to make hydrophobic interaction with Gly11, Gln12, Gly13, Asp32, Thy71, Gln73, Lys107, Phe108, Ile118, and Thr231 residues of BACE. Polyphenolic compounds were found in a study to establish hydrophobic associations with Thr72, Gln73, Asn233, Arg235, Lys238, Ser325, Gln326, Ser327, and Ser328 residues of the BACE.
VGSCs are important pharmaceutical targets for the treatment of neurological disorders such as epilepsy, heart arrhythmias, and chronic pain, and are necessary for the activation and proliferation of potential activity in electrically excitable cells. Topiramate was found to make H-bond and hydrophobic interaction with the important amino acid residue of VGSC. Both H-bond and hydrophobic interactions are vital in the stability of the inhibitor-protein complex.
In the docking studies, a higher (negative) △G value signifies the binding efficiency of a ligand/inhibitor to the target protein. Interestingly, in this study, topiramate exhibits △ G value as −5.67, −5.64 kcal/mol, −5.98 kcal/mol for BACE, VGSC, and CA II, respectively. Topiramate is a potent inhibitor of various CA isozymes including CA II. The binding energy analysis revealed that similar to CA II, topiramate also has almost the same binding efficiency as BACE and VGSC. These results indicate that topiramate may act as a dual inhibitor against BACE and VGSC. Importantly, because epilepsy is associated with AD, developing new BACE inhibitors would be particularly useful.
| Conclusion|| |
This study explores the molecular interaction of topiramate with BACE and VGSC to get insight into its anti-Alzheimer's as well as the antiepileptic effect. Hydrophobic interactions and H-bond exhibit a vital role in the binding of topiramate with the active site of BACE and VGSC. Topiramate was found to follow the lead-likeness property. The findings of this research should be used in the development of dual inhibitors against BACE and VGSC to establish a potential treatment against neurological conditions associated with epilepsy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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