**1. Introduction**

In recent years, psychoactive drug usage has increased worldwide due to the increasing incidence of related psychiatric disorders [1]. However, the most commonly prescribed psychoactive drugs, such as antidepressants, antipsychotics, and mood stabilizers, cause unwanted side effects (excessive systemic drug exposure) and toxicity to human systems [2,3].

Quetiapine (QTP Figure 1A) is a second generation (short-acting atypical) antipsychotic drug of dibenzothiazepine (class), which is used to treat schizophrenia, acute bipolar disorder, and major depression in adolescents and adults [4–7]. The exact mechanism of action of QTP is poorly understood. However, QTP is an antagonist of various neurotransmitter receptors in the brain, such as dopamine D<sup>1</sup> and D2, adrenergic alpha receptors alpha<sup>1</sup> and alpha2, histamine H1, and serotonin 5-HT1A and 5-HT2, respectively [8,9]. Specifically, the antipsychotic and antidepressant effects of QTP are believed to be due to the interactions of the above-mentioned neurotransmitter receptors dopamine (D<sup>1</sup> and D2), adrenergic alpha receptors (α<sup>1</sup> and α2), histamine (H1), and serotonin (5-HT1A and 5-HT2) [9].

**Citation:** Zargar, S.; Wani, T.A.; Alsaif, N.A.; Khayyat, A.I.A. A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic, Biochemical, and Molecular Modeling Approaches. *Molecules* **2022**, *27*, 2589. https://doi.org/10.3390/ molecules27082589

Academic Editor: Rudy J. Richardson

Received: 14 March 2022 Accepted: 13 April 2022 Published: 18 April 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

[9].

adrenergic alpha receptors (α1 and α2), histamine (H1), and serotonin (5-HT1A and 5-HT2)

**Figure 1.** (**A**) chemical structure of QTP; (**B**) molecular structure of HSA. **Figure 1.** (**A**) chemical structure of QTP; (**B**) molecular structure of HSA.

Recent studies explore the insight of binding affinity and mechanism of plasma proteins and drug interactions [10–15]. Recently, nanotechnology has helped explore the interaction mechanisms [16,17]. However, the interaction between the drug proteins (plasma) and their mechanism is vital because they directly affect therapeutic drugs' pharmacodynamic and pharmacokinetic properties in the human system [10]. Moreover, the drug proteins (plasma) interactions help to decipher the therapeutic efficacy, distribution, and bioavailability of therapeutic drugs and assist in enhancing solubility in plasma pro-Recent studies explore the insight of binding affinity and mechanism of plasma proteins and drug interactions [10–15]. Recently, nanotechnology has helped explore the interaction mechanisms [16,17]. However, the interaction between the drug proteins (plasma) and their mechanism is vital because they directly affect therapeutic drugs' pharmacodynamic and pharmacokinetic properties in the human system [10]. Moreover, the drug proteins (plasma) interactions help to decipher the therapeutic efficacy, distribution, and bioavailability of therapeutic drugs and assist in enhancing solubility in plasma protein, reducing toxicity, and protecting against oxidation [18–20].

tein, reducing toxicity, and protecting against oxidation [18–20]. Human serum albumin (HSA) is a principal plasma protein with critical physiological functions and facilitates the transportation of many molecules and metabolites (Figure 1B) [21]. It is a monomeric chain globular plasma protein (585 amino acids residues), and its 3D structure consists of three homologous domains (I-III-A and B subdomains). The essential binding regions for drugs in the HSA are Sudlow's site I (subdomains IIA) and Sudlow's site II (subdomains IIIA) [22–25]. However, there is also Site III (subdomain IB), which is also believed to play an essential role in binding various drugs [26]. Therefore, HSA has multiple binding sites and can bind several different drugs, thus making it a fundamental functional drug carrier [27]. Furthermore, the binding of therapeutic drugs within HSA is commonly reversible via weak interactions such as hydrogen bonding, hy-Human serum albumin (HSA) is a principal plasma protein with critical physiological functions and facilitates the transportation of many molecules and metabolites (Figure 1B) [21]. It is a monomeric chain globular plasma protein (585 amino acids residues), and its 3D structure consists of three homologous domains (I-III-A and B subdomains). The essential binding regions for drugs in the HSA are Sudlow's site I (subdomains IIA) and Sudlow's site II (subdomains IIIA) [22–25]. However, there is also Site III (subdomain IB), which is also believed to play an essential role in binding various drugs [26]. Therefore, HSA has multiple binding sites and can bind several different drugs, thus making it a fundamental functional drug carrier [27]. Furthermore, the binding of therapeutic drugs within HSA is commonly reversible via weak interactions such as hydrogen bonding, hydrophobic forces, ionic interactions, and van der Waal's interactions [28].

drophobic forces, ionic interactions, and van der Waal's interactions [28]. To the best of our knowledge, the interaction binding mechanism of QTP and HSA has still not been investigated. Here, multi-spectroscopic techniques and biochemical and molecular docking approaches were applied to scrutinize the binding properties of QTP with HSA under physiological conditions. However, we considered the possibility of complexation between QTP-HSA, which would explore the pharmacodynamics and pharmacokinetics of QTP. The QTP-HSA interactions reported here would explain the binding mechanism at the molecular level and facilitate efforts to modify new therapeutic To the best of our knowledge, the interaction binding mechanism of QTP and HSA has still not been investigated. Here, multi-spectroscopic techniques and biochemical and molecular docking approaches were applied to scrutinize the binding properties of QTP with HSA under physiological conditions. However, we considered the possibility of complexation between QTP-HSA, which would explore the pharmacodynamics and pharmacokinetics of QTP. The QTP-HSA interactions reported here would explain the binding mechanism at the molecular level and facilitate efforts to modify new therapeutic drugs that optimize their distribution within the human body.

### drugs that optimize their distribution within the human body. **2. Results and Discussion**

### **2. Results and Discussion** *2.1. UV-Vis Absorption Spectroscopy*

*2.1. UV-Vis Absorption Spectroscopy* UV-Vis spectral analyses are carried out to observe the structural and conformational changes in the protein molecule induced by the binding ligands and thus to obtain information about their interaction mechanism. [29]. The UV-Vis absorption spectra of the HSA and HSA-QTP complex are shown in Figure 2. It is apparent from the spectra that HSA exhibits an absorption peak at 280 nm coming from the π-π\* transition of the aromatic UV-Vis spectral analyses are carried out to observe the structural and conformational changes in the protein molecule induced by the binding ligands and thus to obtain information about their interaction mechanism. [29]. The UV-Vis absorption spectra of the HSA and HSA-QTP complex are shown in Figure 2. It is apparent from the spectra that HSA exhibits an absorption peak at 280 nm coming from the π-π\* transition of the aromatic amino acids (tryptophan (W), tyrosine (Y), phenylalanine) [30]. An increase in QTP concentration was accompanied by a slight shift in the absorption wavelength. This blue shift indicates that QTP binding is associated with changes in the local environment of HSA. In addition, there is an increase in UV-absorption intensities of HSA at around 280 nm at increasing concentrations of QTP, and this hyperchromicity suggests the HSA-QTP system formation.

Hyperchromicity at around 280 nm in HSA after QTP addition also confirms that the aromatic amino acid (W and Y) microenvironment changes due to the HSA-QTP complex formation [31,32]. firms that the aromatic amino acid (W and Y) microenvironment changes due to the HSA-QTP complex formation [31,32].

amino acids (tryptophan (W), tyrosine (Y), phenylalanine) [30]. An increase in QTP concentration was accompanied by a slight shift in the absorption wavelength. This blue shift indicates that QTP binding is associated with changes in the local environment of HSA. In addition, there is an increase in UV-absorption intensities of HSA at around 280 nm at increasing concentrations of QTP, and this hyperchromicity suggests the HSA-QTP system formation. Hyperchromicity at around 280 nm in HSA after QTP addition also con-

*Molecules* **2022**, *27*, x FOR PEER REVIEW 3 of 17

**Figure 2.** UV absorption spectra of HSA (5 μM) in the absence and presence of increasing concentrations of QTP (5-30 μM) in the wavelength range 240-410 nm. **Figure 2.** UV absorption spectra of HSA (5 µM) in the absence and presence of increasing concentrations of QTP (5–30 µM) in the wavelength range 240–410 nm.
