Exploring Promising Multi-targeted Drug Candidate for Alzheimer’s Disease from Compounds Based on Benzalaniline with 1,3,4-Oxadiazole Skeleton: An In Silico Modeling and Docking Study

Year 2024, Volume: 11 Issue: 4, 1473 - 1482

Rahul K , Devi Thamızhanban , Hariraj Narayanan

https://doi.org/10.18596/jotcsa.1454468

Abstract

In general, oxadiazole and benzalaniline derivatives have shown promising activity against a variety of diseases. Combining these two scaffolds into a single drug candidate is a strategy that has garnered increasing interest in multi-targeted drug discovery. This study aims to identify potential ligands from benzalaniline derivatives containing 1,3,4-oxadiazole, targeting various proteins associated with Alzheimer’s disease through molecular modeling and docking studies. In silico ADME screening was also performed to predict drug-likeness and blood-brain barrier (BBB) permeability, using the QikProp tool from the Schrodinger suit 2023-1 (Maestro 13.5.128). The crystallographic structure of the molecular targets was obtained from the PDB database, specifically Acetylcholinesterase (PDB ID: 4EY7), Butyrylcholinesterase (PDB ID: 4BDS), Monoamine Oxidase (PDB ID: 2V60), and BACE-1 (PDB ID: 7B1P). The designed ligands demonstrated strong affinity with key amino acid residues and their drug-likeness. Along with BBB permeability, it highlights their potential as inhibitors for these targets. In particular, chloro substitution on benzalaniline, combined with hydroxyl aromatic substitution on oxadiazole, exhibited favorable binding affinity with the four receptors selected for this study. A ligand with 3-Chloro and 3’-hydroxy substitution (R139) displayed a strong binding affinity for acetylcholinesterase, with a docking score of -10.247. When the chloro group was positioned at the second site (R114), it was more effective against butyrylcholinesterase, yielding a docking score of -7.723. Furthermore, a ligand with 3-chloro and 4’-hydroxy substitution showed a superior binding score (-10.545) with MAO-B. All proposed compounds fell within the acceptable ADME range (BBB permeability: QPPMDCK value >500; QPlog BB 3 to 1.2). Based on the data presented in this study, the suggested ligands should be considered as potential inhibitors.

Keywords

1,3,4-oxadiazole, benzal aniline, multi-targeted drug discovery, Alzheimer's disease

Ethical Statement

NA

Supporting Institution

College of Pharmaceutical Sciences, GMC kannur

Project Number

2

References

• 1. Bajaj S, Asati V, Singh J, Roy PP. 1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents. Eur J Med Chem [Internet]. 2015 Jun 5;97:124–41. Available from: <URL>.
• 2. Vaidya A, Pathak D, Shah K. 1,3,4‐oxadiazole and its derivatives: A review on recent progress in anticancer activities. Chem Biol Drug Des [Internet]. 2021 Mar 27;97(3):572–91. Available from: <URL>.
• 3. Qadir T, Amin A, Sharma PK, Jeelani I, Abe H. A review on medicinally important heterocyclic compounds. Open Med Chem J [Internet]. 2022 Apr 28;16(1):e187410452202280. Available from: <URL>.
• 4. Deacon RMJ. A novel approach to discovering treatments for Alzheimer’s disease. J Alzheimers Dis Park. 2014;4(2):142–5.
• 5. Lizard G, Latruffe N, Vervandier-Fasseur D. Aza- and Azo-stilbenes: Bio-isosteric analogs of resveratrol. Molecules [Internet]. 2020 Jan 30;25(3):605. Available from: <URL>.
• 6. Siddiqui A, Dandawate P, Rub R, Padhye S, Aphale S, Moghe A, et al. Novel aza-resveratrol analogs: Synthesis, characterization and anticancer activity against breast cancer cell lines. Bioorg Med Chem Lett [Internet]. 2013 Feb 1;23(3):635–40. Available from: <URL>.
• 7. Alanazi FK, Radwan AA, Aou-Auda H. Molecular scaffold and biological activities of anti-alzheimer agents. Trop J Pharm Res [Internet]. 2022 Apr 28;21(2):439–51. Available from: <URL>.
• 8. Melchiorri D, Merlo S, Micallef B, Borg JJ, Dráfi F. Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy? Front Pharmacol [Internet]. 2023 Jun 2;14:1196413. Available from: <URL>.
• 9. Kumar N, Kumar V, Anand P, Kumar V, Ranjan Dwivedi A, Kumar V. Advancements in the development of multi-target directed ligands for the treatment of Alzheimer’s disease. Bioorg Med Chem [Internet]. 2022 May 1;61:116742. Available from: <URL>.
• 10. Hasan AH, Abdulrahman FA, Obaidullah AJ, Alotaibi HF, Alanazi MM, Noamaan MA, et al. Discovery of novel coumarin-schiff base hybrids as potential acetylcholinesterase inhibitors: Design, synthesis, enzyme inhibition, and computational studies. Pharmaceuticals [Internet]. 2023 Jul 6;16(7):971. Available from: <URL>.
• 11. Alcaro S, Bolognesi ML, García-Sosa AT, Rapposelli S. Editorial: Multi-Target-Directed Ligands (MTDL) as challenging research tools in drug discovery: from design to pharmacological evaluation. Front Chem [Internet]. 2019 Feb 18;7:448718. Available from: <URL>.
• 12. Alarcón-Espósito J, Mallea M, Rodríguez-Lavado J. From hybrids to new scaffolds: the latest medicinal chemistry goals in multi-target directed ligands for alzheimer’s disease. Curr Neurophar-macol [Internet]. 2021 May 27;19(6):832–67. Available from: <URL>.
• 13. Ibrahim M, Gabr M. Multitarget therapeutic strategies for Alzheimer’s disease. Neural Regen Res [Internet]. 2019 Mar 1;14(3):437–40. Available from: <URL>.
• 14. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimer’s Dement Transl Res Clin Interv [Internet]. 2023 Apr 25;9(2):e12179. Available from: <URL>.
• 15. Choubey PK, Tripathi A, Tripathi MK, Seth A, Shrivastava SK. Design, synthesis, and evaluation of N-benzylpyrrolidine and 1,3,4-oxadiazole as multitargeted hybrids for the treatment of Alzheimer’s disease. Bioorg Chem [Internet]. 2021 Jun 1;111:104922. Available from: <URL>.
• 16. Wang Y, Sun Y, Guo Y, Wang Z, Huang L, Li X. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. J Enzyme Inhib Med Chem [Internet]. 2015 Mar 23;31(3):389–97. Available from: <URL>.
• 17. Remya C, Dileep KV, Koti Reddy E, Mantosh K, Lakshmi K, Sarah Jacob R, et al. Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase – Design, synthesis and biological evaluation. Comput Struct Biotechnol J [Internet]. 2021 Jan 1;19:4517–37. Available from: <URL>.
• 18. Mehta S, Pathak SR. In silico drug design and molecular docking studies of novel coumarin derivatives as anticancer agents. Asian J Pharm Clin Res [Internet]. 2017 Apr 1;10(4):335–40. Available from: <URL>.
• 19. Tantoso E, Wahab HA, Chan HY. Molecular docking: An example of grid enabled applications. New Gener Comput [Internet]. 2004 Jun;22(2): 189–90. Available from: <URL>.
• 20. Ali SK, Hamed AR, Soltan MM, El-Halawany AM, Hegazy UM, Hussein AA. Kinetics and molecular docking of vasicine from Adhatoda vasica : An acetylcholinesterase inhibitor for Alzheimer’s disease. South African J Bot [Internet]. 2016 May 1;104:118–24. Available from: <URL>.
• 21. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complex-es. J Med Chem [Internet]. 2006 Oct 1;49(21):6177–96. Available from: <URL>.
• 22. Ban T, Ohue M, Akiyama Y. Multiple grid arrangement improves ligand docking with unknown binding sites: Application to the inverse docking problem. Comput Biol Chem [Internet]. 2018 Apr 1;73:139–46. Available from: <URL>.
• 23. Pissurlenkar R, Shaikh M, Iyer R, Coutinho E. Molecular mechanics force fields and their applications in drug design. Antiinfect Agents Med Chem [Internet]. 2009 Apr 1;8(2):128–50. Available from: <URL>.