Unearthing novel PPAR-γ activators: In silico design of eucalyptol analogues for ulcerative colitis | [Pakistan Journal of Pharmaceutical Sciences • 2025]

Author(s):

1. Ozair Khurram Hashmi: Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

2. Muhammad Hanzla: Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

3. Calvin R. Wei: Department of Research and Development, Shing Huei Group,Taipei,Taiwan

4. Muhammad Aashir Khan: Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

5. Muhammad Wassam Bin Wasim: Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

6. Muhammad Abdullah: Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

7. Syed Hafiz Ahmed: Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

8. Muhammad Osama: Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistanp;Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan

Abstract:

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising prevalence, necessitating novel therapeutics. The peroxisome proliferator-activated receptor gamma (PPAR-?) is a promising target for UC management. This study aimed to identify potent, selective PPAR-? agonists derived from the natural product eucalyptol (1,8-cineole), with reported anti-inflammatory and PPAR-? activating properties but limited clinical utility. A computational workflow encompassing molecular docking of 342 eucalyptol analogues against PPAR-?, pharmacokinetic prediction, and molecular dynamics simulations was employed. Docking revealed five top-scoring hits with higher predicted PPAR-? binding affinities than eucalyptol. AA051 emerged as the most promising candidate, exhibiting the lowest binding free energies (31.16 kcal/mol MMGBSA, -16.53 kcal/mol MMPBSA), favorable ADMET profiles including oral bioavailability, solubility, blood-brain barrier permeability, and conformational stability. AA055 also showed a promising binding profile albeit with initial instability. This study highlights computational approaches in drug discovery, identifying AA051 as a compelling PPAR-? agonist lead for UC therapy, paving the way for experimental validation and optimization of this novel scaffold.

Page(s): 1415-1425

DOI: 10.36721/PJPS.2025.38.4.REG.13103.1

Published: Journal: Pakistan Journal of Pharmaceutical Sciences, Volume: 38, Issue: 4, Year: 2025

Keywords:

molecular docking , natural products , Ulcerative colitis , ADMET , PPAR , agonist , molecular dynamic

References:

[1] Acharya R,Chacko S,Bose P,Lapenna A,Pattanayak SP .2019 .Structure based multitargeted molecular docking analysis of selected furanocoumarins against breast cancer. Sci. Rep, 9(1) : 15743.

[2] Agarwal S and Mehrotra R .2016 .An overview of molecular docking. JSM Chem, 4(2) : 1024-1028.

[3] Ahmed B,Ashfaq UA,Qamar MTU,Ahmad M .2014 .Anticancer potential of phytochemicals against breast cancer: Molecular docking and simulation approach. Bangladesh J. Pharmacol., 9(4) : 545-550.

[4] Bertin B,Dubuquoy L,Colombel JF,Desreumaux P .2013 .PPAR-gamma in ulcerative colitis: A novel target for intervention. Curr. Drug Targets, 14(12) : 1501-1507.

[5] Bhura N,Gupta J,Gupta P .2019 .Molecular docking studies of phytochemicals of basil against SIRT2 as an anti-breast cancer. Plant, 19(2) : 2185-2190.

[6] Caioni G,Viscido A,d'Angelo M,Panella G,Castelli V,Merola C,Frieri G,Latella G,Cimini A,Benedetti E .2021 .Inflammatory bowel disease: New insights into the interplay between environmental factors and PPARγ. Int. J. Mol. Sci, 22(3) : 985.

[7] Daina A,Michielin O,Zoete V .2017 .SwissADME: A free web tool to evaluate pharmacokinetics, druglikeness and medicinal chemistry friendliness of small molecules. Sci. Rep, 7(1) : 42717.

[8] Decara J,Rivera P,López-Gambero AJ,Serrano A,Pavón FJ,Baixeras E,Rodríguez de Fonseca F and Suárez J .2020 .Peroxisome proliferator-activated receptors: Experimental targeting for the treatment of inflammatory bowel diseases. Front, 11 : 730.

[9] Fan C,Basharat Z,Mah K,Wei CR .2024 .Computational approach for drug discovery against Gardnerella vaginalis in quest for safer and effective treatments for bacterial vaginosis. Sci. Rep, 14 : 17437.

[10] Fan C,Memon AAQ,Adhikari P,Osama M,Wei CR .2023 .Revisiting the SARS-COV-2 main protease: A 2023 in Silico Odyssey in search of potential inhibitors. J. Popul. Ther. Clin. Pharmacol, 30(18) : 1032-1049.

[11] Fang J,Wang H,Xue Z,Cheng Y,Zhang X .2021 .PPARγ: The central mucus barrier coordinator in ulcerative colitis. Inflamm. Bowel Dis, 27(5) : 732-741.

[12] Ferretti F,Cannatelli R,Monico MC,Maconi G,Ardizzone S G .2022 .An update on current pharmacotherapeutic options for the treatment of ulcerative colitis. J. Clin. Med, 11(9) : 2302.

[13] Gajendran M,Loganathan P,Jimenez G,Catinella AP,Ng N,Umapathy C,Ziade N,Hashash JG .2019 .A comprehensive review and update on ulcerative colitis. Dis, 65(12) : 100851.

[14] Hoch CC,Petry J,Griesbaum L,Weiser T,Werner K,Ploch M,Verschoor A,Multhoff G,Dezfouli AB,Wollenberg B .2023 .1, 8-cineole (eucalyptol): A versatile phytochemical with therapeutic applications across multiple diseases. Biomed, 167 : 115467.

[15] Izham MNM,Hussin Y,Rahim NFC,Aziz MNM,Yeap SK,Rahman HS,Masarudin MJ,Mohamad NE,Abdullah R,Alitheen NB .2021 .Physicochemical characterization, cytotoxic effect and toxicity evaluation of nanostructured lipid carrier loaded with eucalyptol. BMC Complement. Med, 21 : 1-17.

[16] Kim IS,Silwal P,Jo EK .2023 .Peroxisome proliferator-activated receptor-targeted therapies: Challenges upon infectious diseases. Cells, 12(4) : 650.

[17] Laskowski RA,Moss DS,Thornton JM .1993 .Mainchain bond lengths and bond angles in protein structures. J. Mol. Biol, 231(4) : 1049-1067.

[18] Nguyen TK,Nguyen TNL,Nguyen K,Nguyen HVT,Tran LTT,Ngo TXT,Pham PTV,Tran MH .2022 .Machine learning-based screening of MCF-7 human breast cancer cells and molecular docking analysis of essential oils from Ocimum basilicum against breast cancer. J. Mol. Struct, 1268 : 133627.

[19] Rebhi S,Wei BZ,Lebbal CR,Najjaa S,Sadfi-Zouaoui H,Messaoudi N,A N .2024 .Core proteome mediated subtractive approach for the identification of potential therapeutic drug target against the honeybee pathogen Paenibacillus larvae. , 12 : e17292.

[20] Venkataraman B,Almarzooqi S,Raj V,Bhongade BA,Patil RB,Subramanian VS,Attoub S,Rizvi TA,Adrian TE,Subramanya SB .2023 .Molecular docking identifies 1,8-Cineole (eucalyptol) as a novel PPARγ agonist that alleviates colon inflammation. Int. J. Mol. Sci, 24(7) : 6160.

[21] Wiederstein M and Sippl MJ .2007 .ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res, 35(suppl) : W407-W410.

[22] Wei CR,Osama M,Tahir S M .2025 .A narrative overview of retinoid X receptor inhibitors in chronic disease management. Curr. Drug Res. Rev., 17(3) : 333-342.

Citations

Downloads

Views