EXPLORING NEW MONOAMINO OXIDASE- A (MAO-A) SELECTIVE INHIBITORS FROM CUCURBITO PEPO: A VIRTUAL SCREENING, MOLECULAR DOCKING, MD SIMULATIONS AND ADMET ANALYSIS

MAHENDRA GOWDRU SRINIVASA; SUDEEP D GHATE; R. SHYAMA PRASAD RAO; MANOHAR MAHADEV

doi:10.22159/ijap.2025v17i1.52084

Authors

MAHENDRA GOWDRU SRINIVASA Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutical Chemistry, Mangalore-575018, Karnataka, India https://orcid.org/0000-0001-6105-7025
SUDEEP D GHATE Nitte (Deemed to be University), Center for Bioinformatics, Mangaluru-575018, Karnataka, India
R. SHYAMA PRASAD RAO Nitte (Deemed to be University), Center for Bioinformatics, Mangaluru-575018, Karnataka, India https://orcid.org/0000-0002-2285-6788
MANOHAR MAHADEV Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutics Mangalore-575018, Karnataka, India https://orcid.org/0000-0002-4041-1563

DOI:

https://doi.org/10.22159/ijap.2025v17i1.52084

Keywords:

Antidepressant, Curcubito pepo, Docking, MAO-A

Abstract

Objective: This study aimed to identify potential Monoamine oxidase (MAO) inhibitors from Cucurbita pepo to address the increasing prevalence of neurological and neuropsychiatric disorders, such as stroke, Alzheimer's, Parkinson's, autism, migraines, and depression, by targeting key enzymes involved in neurotransmitter degradation.

Methods: The study utilised molecular docking and pharmacological, physiological, and ADMET property analyses to screen compounds from Cucurbita pepo. Ten promising MAO inhibitors were shortlisted for further analysis. Extensive Molecular Dynamics (MD) simulations were conducted over 100 nanoseconds to assess the stability and dynamic behaviour within the MAO-A complex.

Results: Based on molecular docking results, four shortlisted compounds were identified as potential MAO-A inhibitors. Atomic-level docking studies were used to explore the binding mechanisms of the phytoconstituents within the active site of the MAO-A enzyme. The binding free energies of these compounds ranged from-9.183 to-6.001 kcal/mol. Phytoconstituent Compound C1 had the highest binding affinity with a G score of-9.183 kcal/mol, followed by Compound C2 with a G score of-9.045 kcal/mol. MD simulations further confirmed that both C1 and C2 formed highly stable complexes with MAO-A, suggesting their potential as effective inhibitors.

Conclusion: Compounds C1 and C2 from Cucurbita pepo show promise as stable and effective MAO-A inhibitors. Further experimental validation is required to confirm these findings and evaluate their therapeutic potential in treating neurological disorders.

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References

Reed GM, First MB, Billieux J, Cloitre M, Briken P, Achab S. Emerging experience with selected new categories in the ICD-11: complex PTSD prolonged grief disorder gaming disorder and compulsive sexual behaviour disorder. World Psychiatry. 2022;21(2):189-213. doi: 10.1002/wps.20960, PMID 35524599.

Van Duinkerken E, Snoek FJ, DE Wit M. The cognitive and psychological effects of living with type 1 diabetes: a narrative review. Diabet Med. 2020;37(4):555-63. doi: 10.1111/dme.14216, PMID 31850538.

Deuschl G, Beghi E, Fazekas F, Varga T, Christoforidi KA, Sipido E. The burden of neurological diseases in Europe: an analysis for the global burden of disease study 2017. Lancet Public Health. 2020;5(10):e551-67. doi: 10.1016/S2468-2667(20)30190-0, PMID 33007212.

Luo Z, LV H, Chen Y, XU X, Liu K, LI X. Years of life lost due to premature death and their trends in people with selected neurological disorders in shanghai China 1995-2018: a population based study. Front Neurol. 2021;12:625042. doi: 10.3389/fneur.2021.625042, PMID 33746880.

DE Mendonca Lima CA, DE Leo D, Ivbijaro G, Svab I. Suicide prevention in older adults. Asia Pac Psychiatry. 2021;13(3):e12473. doi: 10.1111/appy.12473, PMID 34114355.

Tsirmpas C, Andrikopoulos D, Fatouros P, Eleftheriou G, Anguera JA, Kontoangelos K. Feasibility engagement and preliminary clinical outcomes of a digital biodata-driven intervention for anxiety and depression. Front Digit Health. 2022 Jul;4:868970. doi: 10.3389/fdgth.2022.868970, PMID 35958737.

Subba R, Sandhir R, Singh SP, Mallick BN, Mondal AC. Pathophysiology linking depression and type 2 diabetes: psychotherapy physical exercise and fecal microbiome transplantation as damage control. Eur J Neurosci. 2021;53(8):2870-900. doi: 10.1111/ejn.15136, PMID 33529409.

Jia E, Bartlett MG. Recent advances in liquid chromatographic methods for the determination of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. Biomed Chromatogr. 2020;34(3):e4760. doi: 10.1002/bmc.4760, PMID 31758582.

Tijani AO, Nunez E, Singh K, Khanna G, Puri A. Transdermal route: a viable option for systemic delivery of antidepressants. J Pharm Sci. 2021;110(9):3129-49. doi: 10.1016/j.xphs.2021.05.015, PMID 34089714.

Robertson L, Bertolini F, Meader N, Davies SJ, Barbui C, Gilbody S. Antidepressants for major depression disorder in older people: a network meta analysis. Cochrane Database Syst Rev. 2019 Sep 5;2019(9):CD013394. doi: 10.1002/14651858.CD013394.

Behl T, Kaur D, Sehgal A, Singh S, Sharma N, Zengin G. Role of monoamine oxidase activity in alzheimer’s disease: an insight into the therapeutic potential of inhibitors. Molecules. 2021;26(12):1-21. doi: 10.3390/molecules26123724, PMID 34207264.

Baweja GS, Gupta S, Kumar B, Patel P, Asati V. Recent updates on structural insights of MAO-B inhibitors: a review on target based approach. Mol Divers. 2024;28(3):1823-45. doi: 10.1007/s11030-023-10634-6, PMID 36977955.

Chamberlain SR, Baldwin DS. Monoamine oxidase inhibitors (MAOIs) in psychiatric practice: how to use them safely and effectively. CNS Drugs. 2021;35(7):703-16. doi: 10.1007/s40263-021-00832-x, PMID 34240393.

Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry. 2001 Feb;3(1):22-7. doi: 10.4088/pcc.v03n0105, PMID 15014625.

Sinha S, Kumar B, Luqman S, Singh DK. Neuroprotective potential of cucurbita maxima duchesne ex poir caeselpenia bunduc (L.) roxb and bombax ceiba linn extracts. S Afr J Bot. 2019;120:319-25. doi: 10.1016/j.sajb.2018.09.027.

Heinrich M, Frei Haller B, Leonti M. A perspective on natural products research and ethnopharmacology in mexico: the eagle and the serpent on the prickly pear cactus. J Nat Prod. 2014;77(3):678-89. doi: 10.1021/np4009927, PMID 24559070.

Adnan M, Gul S, Batool S. A review on the ethnobotany phytochemistry pharmacology and nutritional composition of Cucurbita pepo L. J Phytopharm. 2017;6(2):133-9.

Shokrzadeh M, Azadbakht M, Ahangar N, Hashemi A, Saeedi Saravi SS. Cytotoxicity of hydro alcoholic extracts of Cucurbitapepo and Solanum nigrum on HepG2 and CT26 cancer cell lines. Pharmacogn Mag. 2010;6(23):176-9. doi: 10.4103/0973-1296.66931, PMID 20931075.

Vivek Ananth RP, Mohanraj K, Sahoo AK, Samal A. IMPPAT 2.0: an enhanced and expanded phytochemical atlas of Indian medicinal plants. ACS Omega. 2023;8(9):8827-45. doi: 10.1021/acsomega.3c00156, PMID 36910986.

Mohanraj K, Karthikeyan BS, Vivek Ananth RP, Chand RP, Aparna SR, Mangalapandi P. IMPPAT: a curated database of Indian medicinal plants phytochemistry and therapeutics. Sci Rep. 2018;8(1):4329. doi: 10.1038/s41598-018-22631-z, PMID 29531263.

Malkaje S, Srinivasa MG, Deshpande NS, Navada S, Revanasiddappa BC. An in silico approach: design homology modeling molecular docking MM/GBSA simulations and a dmet screening of novel 1,3,4-oxadiazoles as PLK1inhibitors. Curr Drug Res Rev. 2023;15(1):88-100. doi: 10.2174/2589977514666220821203739, PMID 36017854.

Moorkoth S, Prathyusha NS, Manandhar S, Xue Y, Sankhe R, Pai KS. Antidepressant like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies. Pharmacol Rep. 2021;73(5):1273-86. doi: 10.1007/s43440-021-00252-0, PMID 34181212.

Pirolli D, Righino B, DE Rosa MC. Targeting SARS-CoV-2 spike protein/ACE2 protein-protein interactions: a computational study. Mol Inform. 2021;40(6):e2060080. doi: 10.1002/minf.202060080, PMID 33904240.

Muddagoni N, Bathula R, Dasari M. Homology modelling virtual screening prime mmgbsa autodock identification of inhibitors of FGR protein. Biointerface Res Appl Chem. 2021;11(4):11088-103. doi: 10.33263/BRIAC114.1108811103.

Jayasurya BR, Swathy JS, Dinesh S, Sharma S. Molecular docking and investigation of Boswellia serrata phytocompound as cancer therapeutics to target growth factor receptors: an in silico approach. Int J Appl Pharm. 2023 Apr 21;15(4):173-83. doi: 10.22159/ijap.2023v15i4.47833.

Musfiroh I, Sigalingging OS, Suhandi C, Khairul Ikram NK, Megantara S, Muchtaridi M. In silico study of some flavonoid compounds against ace-2 receptors as anti-COVID-19. Int J App Pharm. 2023;15(4):225-30. doi: 10.22159/ijap.2023v15i4.48109.

Odhar HA, Hashim AF, Ahjel SW, Humadi SS. Virtual screening of FDA-approved drugs by molecular docking and dynamics simulation to recognise potential inhibitors against mycobacterium tuberculosis enoyl acyl carrier protein reductase enzyme. Int J Appl Pharm. 2024;16(1):261-6. doi: 10.22159/ijap.2024v16i1.49471.

Machado RR, Eitzinger J. Laukemann J. MD-Bench: engineering the in core performance of short-range molecular dynamics kernels from state of the art simulation packages. Chemical Physics. 2023;17. doi: 10.48550/arXiv.2302.14660.

Halder SK, Mim MM, Alif MM, Shathi JF, Alam N, Shil A. Oxa-376 and Oxa-530 variants of β-lactamase: computational study uncovers potential therapeutic targets of acinetobacter baumannii. RSC Adv. 2022;12(37):24319-38. doi: 10.1039/d2ra02939a, PMID 36128545.

Azzam KA. Swiss ADME and pk CSM webservers predictors: an integrated online platform for accurate and comprehensive predictions for in silico ADME/T properties of artemisinin and its derivatives. KIMS/CUMR/MShKP. 2023;325(2):14-21. doi: 10.31643/2023/6445.13.

Ghosh S, Tripathi P, Talukdar P. In silico study by using protox-II webserver for oral acute toxicity organ toxicity immunotoxicity genetic toxicity endpoints nuclear receptor signalling and stress response pathways of synthetic pyrethroids. World Sci News. 2019 Jun;132:35-51.

Larit F, Elokely KM, Chaurasiya ND, Benyahia S, Nael MA, Leon F. Inhibition of human monoamine oxidase A and B by flavonoids isolated from two algerian medicinal plants. Phytomedicine. 2018 Feb 1;40:27-36. doi: 10.1016/j.phymed.2017.12.032, PMID 29496172.

Huang C, Xiong J, Guan HD, Wang CH, Lei X, HU JF. Discovery synthesis biological evaluation and molecular docking study of (R)-5-methylmellein and its analogs as selective monoamine oxidase a inhibitors. Bioorg Med Chem. 2019 May 15;27(10):2027-40. doi: 10.1016/j.bmc.2019.03.060, PMID 30975503.

Mehta P, Srivastava S, Sharma M, Singh I, Malik R. Identification of chemically diverse GABAA agonists as potential anti-epileptic agents using structure guided virtual screening ADMET quantum mechanics and clinical validation through off target analysis. Int J Biol Macromol. 2018 Nov 1;119:1113-28. doi: 10.1016/j.ijbiomac.2018.08.032, PMID 30098361.

Liu K, Watanabe E, Kokubo H. Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations. J Comput Aided Mol Des. 2017 Feb;31(2):201-11. doi: 10.1007/s10822-016-0005-2, PMID 28074360.

Mollaamin F, Layali I, Ilkhani AR, Monajjemi M. Nanomolecular simulation of the voltage-gated potassium channel protein by gyration radius study. Afr J Microbiol Res. 2010 Dec 18;4(24):2795-803.