MAO-B structure preparation

The crystal structure of MAO-B (PDB ID: 2C65) was obtained from the Protein Data Bank. The co-crystal ligand was removed, and the prepared protein was saved as pdb format.

Ligands preparation

ZINC, a freely available library of commercially available compounds for virtual screening [14], was used to obtain 200 natural compounds in SDF format. These compounds were then converted to pdbqt format to aid in the virtual screening procedure.

Virtual screening

Structure-based virtual screening has achieved several major achievements in recent years [15-17], making it a commonly used technique in early-stage drug development by most pharmaceutical corporations and several academic institutions. In this investigation, the prepared library was screened against MAO-B using PyRx 0.8 software [18]. The SWISSADME online application was used for ADME computations.

Results

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In this study, 200 natural compounds were screened against the MAO-B. Rasagiline was used as the control compound. The screening of the compound library resulted in 11 hit compounds with binding energy values more favorable than the Rasagiline. Among these 11 compounds, the top four compounds (ZINC899884, ZINC4098705, ZINC14764165, and ZINC18847036) were taken for further details interaction analysis.  

ZINC899884 interacted with Tyr326, Leu171, Leu328, Phe343, Tyr60, Tyr398, Ser59, Gly58, Gly434, Cys172, Tyr435, Ile198, Gln206, and Ile199 residues of MAO-B (Figure 1A), with a binding energy of -8.4 kcal/mol. ZINC4098705 interacted with Tyr398, Ser59, Gly58, Tyr60, Phe343, Leu328, Leu171, Gln206, Ile199, Tyr326, Cys172, Phe168, Ile198, and Tyr435 residues of MAO-B (Figure 1B), with a binding energy of -8.2 kcal/mol. ZINC14764165 interacted with Cys172, Ile199, Phe168, Ile198, Tyr435, Lys296, Gly58, Ser59, Gly57, Tyr60, Tyr398, Phe343, Tyr326, Gln206, Leu328, and Leu171 residues of MAO-B (Figure 1C), with a binding energy of -8.1 kcal/mol. ZINC18847036 interacted with Ile199, Phe168, Ile198, Cys172, Tyr435, Gly434, Gly58, Tyr398, Tyr60, Phe343, Gln206, Leu171, and Tyr326 residues of MAO-B (Figure 1D), with a binding energy of -8.0 kcal/mol. Further, the positive control Rasagiline was found to interact with Cys172, Ile198, Phe168, Ile199, Leu171, Gln206, Tyr326, Phe343, Tyr398, Tyr60, and Tyr435 residues of MAO-B (Figure 1E), with a binding energy of -6.3 kcal/mol.

The physicochemical properties and adherence to drug-like criteria of the top 11 compounds demonstrated that they have the necessary characteristics for future drug candidates (Table 2 and Table 3). 

Discussion

Neurons are essential for brain function and play a critical role in communication [19]. Neurodegeneration is the fundamental pathogenic alteration in many brain illnesses [20], the most common of which being Alzheimer’s disease and PD. Although there are various medications available to treat NDs, the majority of them focus on symptoms rather than the underlying cause. This is largely due to the blood-brain barrier, which prevents roughly 99% of foreign substances from entering the brain. PD is a degenerative neurological ailment marked by tremors, muscle rigidity, and poor balance and coordination. Both hereditary and non-genetic variables contribute to PD, and age is a key risk factor [21,22]. MAO-B overexpression and dopamine deprivation are key pathogenic factors. Inhibiting MAO-B lowers dopamine breakdown and increases its levels in the brain, especially in the early phases, and has anti-Parkinson’s effects via targeting the striatum [9]. In docking studies, high negative binding energy indicates a strong interaction between the ligand and target protein complexes [23-26]. Interestingly, the top-hit compounds have more favorable negative binding energy than Rasagiline (control), indicating that they bind more strongly to MAO-B and can be employed as MAO-B inhibitors. Rasagiline is a strong, irreversible, and selective second-generation MAO-B inhibitor used to treat PD. It has demonstrated significant benefits as a monotherapy in early PD and has neuroprotective effects that are independent of MAO-B inhibition [27]. In this study, Cys172, Ile198, Phe168, Ile199, Leu171, Gln206, Tyr326, Phe343, Tyr398, Tyr60, and Tyr435 residues of MAO-B were found to be important in binding to Rasagiline. Interestingly, the top four compounds (ZINC899884, ZINC4098705, ZINC14764165, and ZINC18847036) were found to bind with the majority of these MAO-B residues, implying that these hits bind to the same MAO-B pocket as Rasagiline.

NPs and traditional medicines are important because of their therapeutic potential in treating a variety of ailments, including cardiovascular problems, diabetes, hypertension, cancer, and NDs [28]. Extensive studies have been undertaken on natural sources such as plants, animals, microorganisms, and marine organisms because they contain a diverse range of bioactive chemicals with complex structures and distinct pharmacological effects [29]. NPs and their isolated molecules have been extensively studied as a main source for drug discovery in the search to generate more effective medications, particularly those that improve human brain function [30]. The compounds identified in this study are natural and have a strong binding energy for MAO-B, making them potential MAO-B inhibitors for the treatment of PD.

This study screened natural compounds against MAO-B. ZINC899884, ZINC4098705, ZINC14764165, and ZINC18847036 compounds exhibited strong binding to MAO-B and interacted with key MAO-B residues. These compounds, like the control Rasagiline, interact with MAO-B via several residues. Furthermore, ADME and drug-like prediction resulted in promising results, indicating that these compounds have a high gastrointestinal absorption property, implying that they could be effective MAO-B inhibitors for PD.

Tables and Figures