IN SILICO STUDY TAURINE DEHYDROGENASE INHIBITOR ACTIVITY OF SOME ARYL-HYDRASONES OF  α-KETOAETHERS

K. F.  Huseynquliyeva; K K.  Badalova; A.M.  Maharramov; N.K.  Shıkhaliyev; A.M.  Qacar; Kh. A.  Garazadə; S.R. Mammadova; Z.  Akram; A. Rauf

doi:10.28942/atuj.v6i1y20026.143

Abstract

Computer-Aided Drug Design has changed the drug development process by improving the pharmacodynamics, pharmacokinetics, and possible side effects. This study uses in silico techniques to assess the biological, pharmacokinetic and toxicological, properties of eight α-ketoether derivatives, including both Z- and E-isomers, synthesized through the solvolysis reaction of dichlorodiazadienes in methanol. This study provides a thorough in silico assessment of these derivatives using programs like SwissADME for physicochemical parameters, ProTox II for toxicity analysis, and PassOnline for biological activity predictions. Among the compounds studied, derivatives 5 (Z-isomer) and 6 (E-isomer) showed significant taurine dehydrogenase inhibitory activity, with a predicted activity value (Pa) of 0.694, indicating strong potential for further development. Moreover, toxicity estimations indicate that these compounds are most likely safe and unlikely to cause liver or cancer issues. According to pharmacokinetics, these derivatives are well-absorbed and are likely to cross the blood-brain barrier (BBB), which makes them strong candidates for neurological problems. In conclusion, the computational findings suggest that derivatives 5 and 6 could be employed in drug development by targeting taurine dehydrogenase because of their high effectiveness and safety.

Full article

INTRODUCTION
Finding new therapeutic substances takes a complex process that includes laboratory research, clinical studies, and their use in medical care. Nonetheless, traditional drug development can take a long time, is costly, and often does not turn out as expected [[1], [2]]. Computational methods have allowed CADD to play an important role in drug discovery, as it speeds up the process of finding drugs that might be effective. By implementing new computational approaches, Computer-Aided Drug Design (CADD) has an important role in modern drug discovery by making it easier to choose promising compounds [[3], [4]]. With help from CADD methods, including,virtual screening, and predictive modelling, researchers look into the biological impact, toxicity, and drug effects of compounds before starting any tests, helping to reduce the costs and time needed for drug development [[5], [6]]. Potentially a class of eight different therapeutic compounds known as α-ketoether derivatives (Table 1), have been discovered after the solvolysis reaction of dichlorodiazadienes in methanol (Figure 1). These compounds, including both Z- and E-isomers, exhibit diverse biological activities, making them suitable candidates for in-depth investigation in drug design [7].Each newly created chemical compound must serve the well-being of people by identifying its potential area of application in the future. Often, these applications involve using chemicals for humans, as they are part of chemical or pharmaceutical industries, or for analyzing and synthesizing things, including drugs. The safety of new chemicals is always the main concern in any discipline [[8], [9]]. If the compounds do not possess hazardous properties, their possible toxicity to the human body must be explored. Following the results, their toxicity class must be determined by using the Hodge and Sterner scale [10]. Industrial production of compounds with low toxicity is permitted.

Historically, scientists checked the possible harm of new chemicals by analyzing their impact on laboratory animals. Nevertheless, the introduction of REACH (Registration, Evaluation and Authorization of Chemicals) has resulted in greater use of methods conducted outside of living organisms to address both morality issues and high costs linked to animal experiments [[11], [12]]. Testing of large chemical quantities (≥10 tons) is prescribed by these new measures, and in vitro studies are needed to assess any dangers to human health [13]. Substances with few toxins and strong biological activities may be considered useful for health treatment in humans. The process, called drug design, is used to develop biologically active chemicals into usable medicines. Using traditional ways to discover new drugs often takes time and costs a lot of money. As a consequence, virtual screening, which forms part of the in silico approach, is now widely used [14]. Thanks to these methods, it is possible to recognise drug candidates faster and more accurately while saving time and costs [5]. One important part of bioinformatics is Computer-Aided Drug Design (CADD), which combines biology, computer skills, and statistics. With the help of algorithms and modelling, it can show how ligands attach to bigger protein molecules, giving useful information about their efficacy and effectiveness in medicine. The first discovery of taurine happened in 1827 when it was found in a bull’s bile (the term Taurus was inspired by the bull). Taurine is not found in the group of amino acids contained in protein. It is well known that taurine (2-aminoethanesulfonic acid) is one of the ‘‘semi-essential’’ amino acids, as it consists of an amino plus sulphur framework and is mainly produced in the liver and kidneys from cysteine and methionine. Taurine can be seen in the retina, brain and spinal cord, heart, and placenta and has numerous functions in the body. Taurine protects organs from damage inflicted by inflammation and oxidative stress in model experiments. Taurine regulates processes like endoplasmic reticulum stress, Ca2+ levels, and activity of neurons in the body at the molecular level. Taurine influences different functions in cells, such as metabolizing energy, controlling gene activity, adjusting fluid levels, managing protein quality, and linking bile acids to other molecules. Notably, research has revealed that taurine may provide positive effects in the treatment of nervous system-related problems such as neurodegenerative disorders, stroke, epilepsy, diabetic nerve damage, and other neurological problems [[15], [16]].

Among its functions, taurine, in the brain, affects neurons’ activity, moderates memory abilities, manages aggression, and helps protect against alcohol. According to Jang et al. in 2017, giving taurine orally at a dose of 1000 milligrams per kilogram of body weight each day can help improve memory and reverse brain changes seen in severe cognitive dementia caused by Alzheimer’s disease [17]. As revealed by Columbia University Irving Medical Center investigators in recent studies, a lack of taurine might be a reason for aging. Studies done on mice, monkeys, and humans have shown that with age, the body’s taurine levels decrease[18]. Taurine dehydrogenase breaks down taurine with the formation of sulfa-acetylaldehyde, ammonia, and acceptors of electrons. The purpose of this study is to investigate eight derivatives in terms of their toxicology, biology, and pharmacokinetics, by considering their potential to function as taurine dehydrogenase inhibitors. Taurine, which is an amino acid with sulphur, is needed for multiple body activities [[19], [20], such as neurotransmission modulation [21], maintaining cell balance [22] and shielding the body from stress caused by reactive oxygen species [[15], [22]]. Having low taurine can result in several neurological issues, so taurine dehydrogenase and other relevant enzymes could be considered as possible treatments [15]. Despite knowing much about taurine and α-ketoether derivatives, there is very little insight found in chemical literature on their use as taurine dehydrogenase inhibitors. This study aims to resolve this issue by checking if these compounds can inhibit taurine dehydrogenase, an important enzyme needed for taurine metabolism. By analyzing the chemical, biological, and pharmacokinetic features of these derivatives, we intend to pick out good candidates for medicines that address neurological conditions related to taurine.

METHODOLOGY
In Silico Predictions of Toxicity and Biological Activity
The toxicity and biological activity for the eight α-ketoether derivatives (KEA), Z- and E-forms both, were studied using the PassOnline program (http://www.way2drug.com/passonline/). Using PassOnline, scientists can observe structure-activity relations and find out the possible biological activities of up to 45,000 chemicals. The estimates for each class are given in terms of the probability of an observation being active (Pa) or inactive (Pi), both of these ranging from zero to one. A higher Pa value and lower Pi value indicate a higher likelihood of detecting activity in the experiment.

Canonical SMILES Generation
Using the PassOnline software, the canonical SMILES (Simplified Molecular-Input Line-Entry System) for each of the α-ketoether derivatives have been generated.

Physicochemical and Pharmacokinetic Properties
The physicochemical properties and pharmacokinetic ADME (Absorption, Distribution, Metabolism, and Excretion) studies of the α-ketoether derivatives were performed using the SwissADME program (http://www.swissadme.ch/) and Swiss Target Prediction program (http://www.swisstargetprediction.ch/) [23]. The SwissADME software provided valuable information regarding molecular properties such as solubility, lipophilicity, and other essential characteristics. The Swiss Target Prediction tool was used to predict the potential biological targets for each compound.

Toxicity Prediction
To predict the toxicity of compounds 5 and 6, ProTox II (https://tox-new.charite.de) was used to find the probability of these compounds having any of the following effects: hepatotoxicity, carcinogenicity, and organ-related toxicities [24]. It should be noted that earlier studies were conducted with the creation of pyrazine substitutes to predict the activities of taurine inhibitors with the Pass program [25].

RESULTS
Canonical SMILES
With PassOnline software, the standard SMILES all the α-ketoether have been determined and summarized in Table 2. Pharmacokinetic Predictions (ADME) Pharmacokinetic properties, including ADME, are key determinants in evaluating the drug-likeness of chemical compounds. In this study, we used SwissADME software to estimate the pharmacokinetic traits and physicochemical properties of eight α-ketoether derivatives. Such predictions are crucial because they help us know how compounds will interact with the body and what risks they may carry.

Physicochemical Descriptors and Pharmacokinetic Properties
The SwissADME tool provides vital information, including the Molar Refractivity (MR) for each compound, as well as Total Polar Surface Area (TPSA), Log P (lipophilicity), and solubility predictions. These predictions are used to decide if a compound is likely to be well absorbed, distributed through the body, and generally available. Table 3 estimates the Molar Refractivity, Total Polar Surface Area, and Log P values for all eight α-Ketoether derivatives.Solubility Predictions Solubility is a critical factor in determining whether a compound can be absorbed by the body. The SwissADME software also predicts solubility in various environments, using ESOL and Ali Solubility methods. Table 4 presents the predicted solubility for each compound.Gastrointestinal Absorption, Blood-Brain

Barrier Permeability, and Metabolism
Pharmacokinetics was investigated further by considering the absorption through the GI tract, passage through the BBB, and how each compound is metabolized. These values explain how absorption will progress, whether the compound may penetrate the blood-brain barrier, and if metabolism could occur. All these compounds have high GI absorption, which means they are likely to be absorbed well in the gut. Additionally, all the tested derivatives are expected to cross the BBB, so they could help treat nervous system diseases (Table 5). Bioavailability, Lipinski Rule, Veber Rule, and Ghose Rule Predictions. The bioavailability score, Lipinski's Rule of Five, and Veber and Ghose's rules were used to predict whether the compounds possess desirable characteristics for oral drug administration.Bioavailability Score: All derivatives are thought to have a moderate likelihood of getting into the bloodstream because their bioavailability score is 0.55. Having a high score usually reflects that the drug can be absorbed more effectively (Table 6).Lipinski’s Rule of Five: Lipinski’s Rule considers a few molecular attributes (such as weight, the ability to take part in hydrogen bonding, and Log P) when evaluating the compounds. In all cases, the XLOGP3 of these drugs is more than 3.5, which suggests that their ability to travel through and be absorbed by the body may be restricted. Nevertheless, these necessary features are still met by these compounds since they do not have any violations in the number of hydrogen bond donors and acceptors (Table 6). Veber and Ghose Rules: According to the Veber Rule (which underlines factors such as rotatable bonds and polarity on the surface) and the Ghose Rule (which pays attention to molecular size and polarity), these derivatives fall within the desired ranges for drugs that can be taken by mouth. While a few of the derivatives have a violation for XLOGP3 exceeding 3.5, their overall molecular characteristics indicate they can still be orally absorbed well (Table 6). Synthetic Accessibility: The fact that all compounds are marked as having “Yes” for synthetic accessibility allows us to assume that they are suited for effective drug development (Table 6). PAINS Alerts: PAINS alerts are the same for all compounds, as they often have building blocks that tend to bind with multiple partners and could make it hard for the molecules to be used as effective drugs (Table 6).Biological Activity and Toxicity Predictions Using the PassOnline program, the researchers focused on evaluating the α-ketoether derivatives as potential inhibitors of Taurine Dehydrogenase (TDH). The program also calculated toxicity values for each compound (LD50 and toxicity class), an important factor used to determine their safety. The results, summarized in Table 7, indicate that while all compounds show varying levels of TDH inhibition (Pa values), the KEA 5 and 6 isomers exhibited the highest inhibitory activity, with a Pa value of 0.694, which corresponds to approximately 70% inhibitory activity. This makes them the most promising candidates for further drug development targeting taurine dehydrogenase inhibition.

DISCUSSION
Concerning their possible taurine dehydrogenase enzyme inhibitors, this research provides an extensive in silico study on eight α-ketoether derivatives analyzing their biological, pharmacokinetic, and toxicological profiles. To assess the efficacy of these compounds as potential taurine dehydrogenase drugs, predicted toxicity of compounds, and performed ADME profiling. Using the SwissADME tool, pharmacokinetic forecasts were produced that showed all derivatives had great ability to pass the blood-brain barrier (BBB) and strong gastrointestinal absorption (GI). Given that both qualities are essential for chemicals meant to target the nervous system [23], this makes them excellent candidates for the treatment of neurological conditions. Furthermore predicted to be metabolized by several cytochrome P450 (CYP) enzymes, the molecules' possible efficient body processing is supported [6]. Toxicity predictions, employing ProTox II, showed Derivatives V and VI to be very promising, with low levels of toxicity and low risks for hepatotoxicity and carcinogenicity. This is a significant discovery in the drug development process, as it implies that these compounds will have fewer possibilities of inducing serious adverse effects, a key consideration when deciding on a compound for therapeutic purposes. The immunotoxicity and cytotoxicity predictions were also positive, suggesting that such derivatives would be safer than conventional drugs, which are usually associated with high toxicity levels [11]. Nonetheless, more in vivo experiments should be conducted to confirm these predictions and determine the safety of the compounds in actual biological systems [13]. PassOnline was utilized to explore the activity of the compounds, confirming that V and VI gave the greatest taurine dehydrogenase inhibition with a Pa value of 0.694. Because these substances block inhibitory activity strongly, they are especially valuable for treating neurological disorders since taurine protects the brain and supports its function. Some neurological issues, particularly Alzheimer’s disease, are connected to a lack of taurine, which makes taurine dehydrogenase inhibitors an interesting option for treatment [[15], [18]]. This study increases medical experts’ knowledge about using taurine-focused drugs, encouraging them to create new drugs that control taurine levels. As scientists previously found, taurine is important for the brain and taurine dehydrogenase inhibitors have potential medicinal effects. Besides, the practice ADME predictions shows new ways used in drug discovery nowadays. Thanks to these tools, scientists can predict the success, risks, and how drugs will move in the body even before they are fully developed, which hastens the process and reduces expenses [[1, [5]]. To conclude, the research found that certain α-ketoether derivatives have strong activity against taurine dehydrogenase, a good pharmacokinetic profile, and a low risk of toxicity. Specifically, V and VI derivatives appear to have the potential to be used as drugs that target taurine dehydrogenase for neurological therapy. These findings indicate that using in silico methods is important in drug discovery since they help identify the most promising drugs without spending too much time or money.

CONCLUSIONS
Based on in silico or CADD predictions, toxicological properties, biological activities, physicochemical properties and pharmacokinetic ADME parameters of 8 derivatives, including Z- and E-isomers of α-ketoethers aryl hydrozos (KEA) from the solvolysis reaction of dichlorodiazadienes in methanol, were virtually investigated. In silico predictions of compounds used the PassOnline program, physicochemical properties and pharmacokinetic ADME predictions were studied using SwissADME and Swiss TargetPrediction, and toxicity indicators were studied using ProTox II programs. It was determined that KEA 5 – methyl (Z)-2-(4- dimethylamino)phenyl)-2-(2-(p-tolyl)hydrazineyldene) acetate and 6 – methyl (E)- 2-(4-dimethylamino)phenyl)-2-(2-(p-tolyl) hydrazineylidene acetate chemical compounds demonstrate more TDH inhibitory activity (Pa – 0.694). According to Lipinski's "rule of five" (Ro5), the obtained indicators for the investigated chemical compounds yield positive results. Thus, n-octanol/water partition coefficient: logP ≤ 5, the molecular weight: MW ≤ 500 g/mol, the number of hydrogen bond acceptors: HBA ≤ 10, the number of hydrogen bond donors: HBD ≤ 5, a number of rotatable bonds: NRB ≤ 10.

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References

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