Molecular Docking Studies of Substituted Aromatic...

[Full title: Molecular Docking Studies of Substituted Aromatic N-(3-chloro-4-fluorophenyl)-1- phenylmethanimine Derivatives against Monoamine Oxidase-B as Potential Anti-parkinsonian Agents]

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Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 899 Molecular Docking Studies of Substituted Aromatic N-(3-chloro-4-fluorophenyl)-1- phenylmethanimine Derivatives against Monoamine Oxidase-B as Potential Anti-parkinsonian Agents Sony Jangam 1 , Dandamudi Alekhya 2 , Satya Sree Bandaru 3 , Shaik Khadar Yazdan 4 , T. Samanvai 5 , Ravi Chandra Sekhara Reddy Danduga 6 , Podila Naresh 7 , Vijaya Kishore Kanakaraju 1 1 Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India, 2 Department of Pharmaceutical Chemistry, Krishna University College of Pharmaceutical Sciences and Research, Machilipatnam, Andhra Pradesh, India, 3 Department of Pharmaceutical Chemistry, V. V. Institute of Pharmaceutical Sciences, Gudlavalleru, Andhra Pradesh, India, 4 Department of Pharmaceutical Chemistry, Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Chowdavaram, Guntur, Andhra Pradesh, India, 5 Department of Pharmaceutical Chemistry, Viswanadha Institute of Pharmaceutical Sciences, Visakhapatnam, Andhra Pradesh, India, 6 Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, Maharashtra, India, 7 Department of Pharmaceutical Sciences, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh, India Abstract Introduction: In recent times, Parkinson’s disease has been considered a major problem in most of the men than women. The monoamine oxidase-B (MAO-B) inhibitors show anti-Parkinsonian activity. This study describes a range of substituted aromatic N-(3-chloro-4-fluorophenyl)-1-phenylmethanimine derivatives that have been designed and docked against the MAO-B enzyme to evaluate their potential anti-Parkinson’s agents. Comparison was made between the ligands and common MAO-B inhibitors such as selegiline, rasagiline, and safinamide. Materials and Methods: First, with the help of Chemsketch software, the ligands were drawn and saved in.mol format, and they were converted to .pdb format using Avogadro software. iGEMDOCK software was used to perform molecular docking studies and docked compounds were visualized through BIOVIA Discovery Studio Visualizer. Results and Discussion: Most of the substances were found to have enhanced MAO-B enzyme binding affinities. The majority of the ligands have demonstrated greater binding energies when compared with the standard MAO-B inhibitors, such as safinamide (−102.64 K.cal/mol), selegiline (−74.38 K.cal/mol), and rasagiline (−72.76 K.cal/mol). Compounds C 23 (−120.20 K.cal/mol) and C 33 (−116.97 K.cal/mol) were found to have superior binding energies compared to the standard MAO-B inhibitors and so were chosen for visualization. Conclusion: Derivatives of substituted aromatic N-(3-chloro-4-fluorophenyl)-1- phenylmethanimine showed a higher binding affinity toward the MAO-B enzyme than standard inhibitors, suggesting that they might be considered for the treatment of Parkinson’s disorder Address for correspondence: Vijaya Kishore Kanakaraju, Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India. Phone: 9948442452. E-Mail: drvijayakishore@gmail.com Received: 25-07-2024 Revised: 15-09-2024 Accepted: 27-09-2024 ORIGINAL AR TICLE Keywords: BIOVIA discovery studio visualizer, iGEMDOCK software, MAO-B inhibitors, molecular docking, Parkinson’s disease, substituted aromatic N-(3-chloro-4- fluorophenyl)-1-phenylmethanimine INTRODUCTION I n the current study, docking studies were conducted on aromatic compounds, such as benzaldehyde derivatives, which have demonstrated a stronger affinity toward

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Jangam, et al .: Molecular docking studies of phenylmethanimine derivatives against MAO-B Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 900 Parkinson’s disease. The chemical compound benzaldehyde (C 6 H 5 CHO) consists of a benzene ring along with a formyl substituent. In industry, it is one of the most often utilized aromatic aldehydes. It is a colorless liquid with a distinct almond-like odor that is frequently used in cherry-flavored sodas It was reported that benzaldehyde derivatives exhibit a variety of activities, including antimicrobial, analgesic, anti-inflammatory, [1] antihypertensive, [2] and antitumor effects [3] The basis for this study is to prove that the substituted aromatic N-(3-chloro-4-fluorophenyl)-1-phenylmethanimine derivatives exhibit antiparkinsonian activity because they increase dopamine levels. Monoamine oxidase-B (MAO-B) inhibitors improve dopamine utilization in nerve cells. Oxidative stress and dopamine turnover are decreased when this enzyme is inhibited. To treat the symptoms of Parkinson’s disorder, MOA-B inhibitors increase the amount of dopamine that is available [4-11] The current work attempts to assess different designed substituted aromatic N-(3- chloro-4-fluorophenyl)-1-phenylmethanimine derivatives against the MAO-B enzyme for anti-Parkinson’s disease in an in silico manner. MATERIALS AND METHODS The General Scheme for Substituted Aromatic N-(3-chloro-4-fluorophenyl)-1-Phenylmethanimine Derivatives: [12,13] As per the original scheme, [12] the thiophene-2-carboxaldehyde was replaced with various benzaldehyde derivatives and with 3-chloro-4-fluoro aniline to give the final products. A number of benzaldehyde derivatives were chosen from the aforementioned scheme, [12,13] and the final products were designed in accordance with the scheme. Using SwissADME software, [14-19] the ADME properties of the designed vast library of compounds were predicted after they underwent screening using TopKat software [16-20] for in silico toxicity. The designed compounds showed excellent ADME properties Figure 1: PDB ID: 2 BYB and exhibited non-carcinogenicity and non-toxicity and later these compounds were chosen for docking studies From the above data, it was understood that all the [Table 1] test and standard compounds have better ADME properties Molecular Docking The 2 D structure of the ligand was created using Chemsketch software and saved in.mol format. Then these ligands were saved as .pdb format using the Avogadro tool [16-19,21] The final compounds were designed using previously stated scheme and the targets were predicted with the help of Swiss target prediction software [16-19,22] The majority of the compounds indicate that the MAO-B enzyme was a possible primary target. As Parkinson’s disease can be treated with MAO-B inhibitors, the main aim of the current study is to determine whether or not MAO-B enzyme inhibition by the test ligands is possible for antiparkinsonian activity. The compounds were tested for their ability to inhibit the MAO-B enzyme, and their results were contrasted with those of standard inhibitors, namely selegiline, rasagiline, and safinamide. To assess the molecular interactions for chosen safe compounds with MAO-B enzyme [Figure 1] (PDB ID: 2 BYB complex with ligand deprenyl), which was acquired through the Protein Data Bank and in silico docking studies were performed To assess binding positions and interactions for the generated compounds, docking studies were conducted. The software used for it was iGEMDOCK version 2.1 [16-19,23] iGEMDOCK refers to the genetic evolutionary method for molecular docking. A graphical-automated drug design system for docking, screening, and analysis is called iGEMDOCK. This software calculates the orientation and conformation of ligands with respect to the protein’s active site. To assess binding affinities and molecular interactions, docking simulations were performed. Using in silico toxicity prediction, a total of 39 safe and non-carcinogenic compounds were found. These compounds were chosen for molecular docking in addition to standard MAO-B inhibitors such as safinamide, [24-30] rasagiline, [31-37] and selegiline [38-41] Both the standard and accurate docking methods were followed. Regarding the basis of the scoring function, the most effective docking solutions were analyzed. By integrating

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Jangam, et al .: Molecular docking studies of phenylmethanimine derivatives against MAO-B Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 901 hydrogen bonding, Vander Waals, and electrostatic energies, the scoring function was calculated. The interactions between the ligand and target protein were determined by a postdocking interaction profile analysis of the best poses. The top 10 compounds with higher binding energies were chosen, and the top most two compounds with higher binding energies and molecular interaction profiles were taken for post-docking interaction analysis. The ligand interactions were visualized and analyzed using Biovia Discovery Studio Visualizer RESULTS AND DISCUSSION Scheme for the Synthesis of N - (3-chloro-4- fluorophenyl)-1-(3-nitrophenyl) Methenamine and N-(3-chloro-4-fluorophenyl)-1-(3,4- dimethoxyphenyl) methenamine The green color in the above table represents hydrogen bonding residues and the red color represents unfavorable bumps Figure 2: Visualization data of standard MAO-B Inhibitors such as safinamide, selegiline, and rasagiline along with top compounds C 23 and C 33 Figure 3: Binding pocket analysis for C 23, C 33, safinamide, selegiline, and rasagiline

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Jangam, et al .: Molecular docking studies of phenylmethanimine derivatives against MAO-B Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 902 Table 2: Summary of interactions and binding energies of compounds with MAO-B Compound Code Binding energy (K.Cal/mol) Interacting active site residues C 23 −120.205 CYS 172 , TYR 60, GLY 434, TYR 188, PHE 168, GLN 206, ILE 198, TYR 326, LEU 171, ILE 199, TYR 398, TYR 435 C 33 −116.972 GLY 434 , PHE 168, CYS 172, TYR 60, PHE 343, TYR 326, LEU 171, TYR 435, ILE 199, TYR 398 C 27 −113.622 TYR 398, TYR 188 , GLN 206, LYS 296, ILE 198, GLY 434, TYR 60, PHE 343, ILE 199, TYR 326, LEU 171, TYR 435, CYS 172, PHE 168 C 39 −111.267 TYR 435 , TYR 60, TRP 119, PHE 168, TYR 188, GLN 206, LEU 328, MET 341, ILE 199, LEU 171, TYR 326, PHE 343, TYR 398, CYS 172 C 07 −111.21 TYR 435, PHE 168 , GLY 434, TYR 188, GLN 206, LEU 171, ILE 199, TYR 326, TYR 398, CYS 172 C 21 −108.372 ILE 199 , TYR 60, TYR 188, GLN 206, TYR 326, GLY 434, CYS 172, PHE 168, LEU 171, ILE 198, TYR 435, TYR 398 C 38 −107.939 CYS 172, PHE 168, TYR 435 , TYR 60, ILE 198, GLN 206, ILE 316, PHE 343, TYR 326, TYR 398, ILE 199, LEU 171 C 13 −107.604 CYS 172, TYR 435 , PHE 168, ILE 198, GLN 206, TYR 398, LEU 171, TYR 60, ILE 199, ILE 316, TYR 326 C 08 −107.362 CYS 172, TYR 398, TYR 60, PHE 343, GLN 206, TYR 435, PHE 168, ILE 199, LEU 171, TYR 326 C 04 −106.954 ILE 316, TYR 60, LEU 167, TRP 119, LEU 164, PHE 343, TYR 435, ILE 198, TYR 326, ILE 199, PHE 168, GLN 206, TYR 398, LEU 171, CYS 172 C 06 −106.458 TYR 60, LEU 164, ILE 198, ILE 316, PHE 343, TYR 326, TYR 435, TRP 119, PHE 168, ILE 199, CYS 172, LEU 171, GLN 206, TYR 398 Safinamide −102.647 TYR 188, TYR 435, ILE 199 , CYS 172, LEU 171, TYR 398, TYR 326 Selegiline −74.3821 GLY 434, GLN 206 , TYR 398, TYR 435, LEU 171, TYR 326 Rasagiline −72.7638 ILE 199 , PHE 168, ILE 198, GLN 206, PRO 102, THR 314, THR 201, SER 200, ILE 316, CYS 326, LEU 171 Table 1: ADME data for the top two compounds along with standard MAO‑B inhibitors Parameters C 23 C 33 Standard-1 (Safinamide) Standard-2 (Selegiline) Standard-3 (Rasagiline) Molecular weight 278.67 g/mol 293.72 g/mol 302.34 g/mol 187.28 g/mol 171.24 g/mol Hydrogen bond donors 0 0 2 0 1 Hydrogen bond acceptors 4 4 4 1 1 Lipophilicity <5 <5 <5 <5 <5 DISCUSSION The binding energies of nearly all the top most 10 compounds are higher than those of standard MAO-B inhibitors. Among them [Table 2], C 23 and C 33 have binding energies that are higher than those of standard MAO-B inhibitors such as safinamide, rasagiline, and selegiline. Comparing the binding energies of compound C 23 (−120.205 K.Cal/mol) and compound C 33 (−116.972 K.Cal/mol) with standard MAO-B inhibitors, such as safinamide (−102.647 K.Cal/mol), selegiline (−74.3821 K.Cal/mol), and rasagiline (−72.7638 K.Cal/mol). It is evident that these compounds performed significantly better in virtual screening and molecular docking The Figure 2 shows in the C 23 compound exhibits one H-bond interaction with the CYS:172 (4.28 A o ) residue. Pi-sigma interaction with the LEU:171. TYR:435 and TYR:398 with pi-sulfur interaction. Pi-alkyl and alkyl interactions with TYR:326 and rest are Vander Waal’s interactions.Figure 2 shows in the C 33 had one H-bond interaction with GLY:434(3.66 A o ), pi-sigma interaction with TYR:435, LEU:171, pi-pi stacked interactions with TYR:398, pi-alkyl and alkyl interactions with CYS 172, TYR 60, PHE 343, and TYR 326 and then the other had a Vander Waal’s interaction with PHE:168 Previous literature [42] revealed that two amino acids TYR:398 and TYR:435 are responsible for better binding affinity of

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Jangam, et al .: Molecular docking studies of phenylmethanimine derivatives against MAO-B Asian Journal of Pharmaceutic s • Jul-Sep 2024 • 18 (3) | 903 the ligands with the MAO-B enzyme. Similarly, in our compounds, these two amino acids have interaction with the MAO-B enzyme. Similarly, standard MAO-B inhibitors safinamide and selegiline also have interaction with TYR:398 and TYR:435 with that of MAO-B active site pocket Since [Figure 3] C 23 and C 33 are positioned inside the active site pocket, their orientations are superior to those of standard MAO-B inhibitors, namely rasagiline, selegiline, and safinamide. C 23 might have higher binding affinity because it contains stronger electron-withdrawing groups such as NO 2 , Cl, and F. There is better binding energy in compound C 33, it might be due to the existence of electron-withdrawing groups such as OCH 3 , Cl, and F CONCLUSION Based on all these supportive data, compounds C 23 and C 33 have higher binding affinities. 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Oxidative stress, Parkinson's disease, Molecular docking, Binding affinity, Molecular weight, Hydrogen bonding, Antiparkinsonian activity, Binding Affinities, Scoring Function, Molecular docking studies, Benzaldehyde, Chemsketch software, Active site, Virtual screening, IGEMDOCK software, Protein data bank, Molecular interaction, Binding energies, In Silico, Binding pocket, Hydrogen bond, ADME properties, Hydrogen bond acceptor, Docking simulation, Electron withdrawing group, Dopamine level, Lipophilicity, Hydrogen bond donor, Ligand, Monoamine oxidase B, Selegiline, Rasagiline, Active Site Residues, In-vivo activities, Benzaldehyde derivatives, Benzene ring, MAO-B inhibitor, Nerve cell, Parkinson's disorder, BIOVIA Discovery Studio Visualizer, Unfavorable bump, Pi-alkyl interaction, Pi sigma interaction.