Novel Phytochemical Inhibitors of Leptin: A Molecular Docking Approach for Potential Cardiovascular and Antidiabetic Therapies
Keywords:
Phytochemical Inhibitors, Leptin, Molecular Docking, Cardiovascular, Antidiabetic TherapiesAbstract
OBJECTIVE: To identify phytochemicals as potential leptin inhibitors, particularly in the context of immune and cardiovascular health, using molecular docking analysis.
METHODOLOGY: This study was conducted from 2023 to 2024 with the joint efforts of the Department of Bioinformatics and Biotechnology, Government College University Faisalabad, and the Center of Excellence and Molecular Biology, University of Punjab Lahore. The 3D structure of Leptin was retrieved from the Protein Data Bank and refined for docking analyses using PyRx. A ligand library consisting of 5,006 phytochemicals was prepared from various databases. The interactions were visualized using Discovery Studio. Compounds with high docking scores were further analyzed for their ADMET properties, based on Lipinski's Rule of Five, to ensure their drug-like characteristics and predict their safety profiles.
RESULTS: The compounds Peonidin, Diosmin, 7-[3-(3-hydroxy oct-1-enyl)-4,6-dioxabicyclo[3.1.1]heptan-2-yl]hept-5-exonic acid, Carnitine, Dihydrodaidzin, 4-dimethylpodophyllotoxin, 4-demethyldeoxypodophyllotoxin, (+)-sophorol and Tylophorinidine demonstrated successful binding to the Leptin. Thus, it potentially interferes with the leptin-leptin receptor interaction. Diosmin and Dihydrodaidzin showed the most vital binding score of -7.9 Kcal/mol of all the top-ranking compounds.
CONCLUSION: These compounds may act as effective inhibitors of Leptin, which may help develop natural, affordable therapies for cardiovascular disorders and diabetes. However, further research is required to validate their efficacy and safety.
References
Vilariño-García T, Polonio-González ML, Pérez-Pérez A, Ribalta J, Arrieta F, Aguilar M et al. Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes. Int J Mol Sci. 2024; 25(4): 2338.
Askarpour M, Alizadeh S, Hadi A, Symonds ME, Miraghajani M, Sheikhi A et al. Effect of Bariatric Surgery on the Circulating Level of Adiponectin, Chemerin, Plasminogen Activator Inhibitor-1, Leptin, Resistin, and Visfatin: A Systematic Review and Meta-Analysis. Horm Metab Res. 2020; 52(4): 207-15.
Bruder-Nascimento T, Kress TC, Kennard S, Belin de Chantemele EJ. HIV Protease Inhibitor Ritonavir Impairs Endothelial Function Via Reduction in Adipose Mass and Endothelial Leptin Receptor-Dependent Increases in NADPH Oxidase 1 (Nox1), C-C Chemokine Receptor Type 5 (CCR5), and Inflammation. J Am Heart Assoc. 2020; 9(19): e018074.
Travers RL, Trim WV, Motta AC, Betts JA, Thompson D. Calorie restriction-induced leptin reduction and T-lymphocyte activation in blood and adipose tissue in men with overweight and obesity. Int J Obesity. 2024: 1-10.
Chang ML, Hsu CM, Tseng JH, Tsou YK, Chen SC, Shiau SS et al. Plasminogen activator inhibitor-1 is independently associated with non-alcoholic fatty liver disease, whereas Leptin and adiponectin vary between genders. J Gastroenterol Hepatol. 2015; 30(2): 329-36.
Clausen T, Djurovic S, Reseland JE, Berg K, Drevon CA, Henriksen T. Altered plasma concentrations ofLeptin, transforming growth factor-beta(1) and plasminogen activator inhibitor type 2 at 18 weeks of gestation in women destined to develop pre-eclampsia. Circulating markers of disturbed placentation? Placenta. 2002; 23(5): 380-5.
Chiriacò M, Nesti L, Flyvbjerg A, Golay A, Nazare J-A, Anderwald C-H et al. At any level of adiposity, relatively elevated leptin concentrations are associated with decreased insulin sensitivity. J Clin Endocrinol Metabol. 2024; 109(2): 461-70.
Douros JD, Baltzegar DA, Breves JP, Lerner DT, Seale AP, Gordon Grau E et al. Prolactin is a major inhibitor of hepatic Leptin A synthesis and secretion: studies utilizing a homologous Leptin A ELISA in the tilapia. Gen Comp Endocrinol. 2014; 207: 86-93.
?im?ir IY, Özgür S, Soyalt?n UE, Çetinkalp ?. Effect of Dopamine Agonist Treatment on Glycemic Control in Patients with Lipodystrophy. Endocrinol Res Pract. 2024; 28(3).
Eiden S, Daniel C, Steinbrueck A, Schmidt I, Simon E. Salmon calcitonin - a potent inhibitor of food intake in states of impaired leptin signalling in laboratory rodents. J Physiol. 2002; 541(Pt 3): 1041-8.
Engin A. The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective. Obesity and Lipotoxicity. 2024: 463-87.
Gelsomino L, Giordano C, Camera G, Sisci D, Marsico S, Campana A et al. Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages. Biomolecules. 2020; 10(4).
Gerrits AJ, Gitz E, Koekman CA, Visseren FL, van Haeften TW, Akkerman JW. Induction of insulin resistance by the adipokines resistin, Leptin, plasminogen activator inhibitor-1 and retinol-binding protein 4 in human megakaryocytes. Haematologica. 2012; 97(8): 1149-57.
Marques L, Costa B, Pereira M, Silva A, Santos J, Saldanha L et al. Advancing precision medicine: A review of innovative In Silico approaches for drug development, clinical pharmacology and personalized healthcare. Pharmaceutics. 2024; 16(3): 332.
Barros MT, Paci M, Tervonen A, Passini E, Koivumäki JT, Hyttinen J et al. From multiscale biophysics to digital twins of tissues and organs: future opportunities for in-silico pharmacology. IEEE Transact Mol Biol Multiscale Comm. 2024.
Olmedo DA, Durant-Archibold AA, López-Pérez JL, Medina-Franco JL. Design and Diversity analysis of chemical libraries in drug discovery. Combin Chem High Screen. 2024; 27(4): 502-15.
Hosaka S, Yamada T, Takahashi K, Dan T, Kaneko K, Kodama S et al. Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain via Alleviation of Hypothalamic Leptin Resistance. Front Pharmacol. 2020; 11: 943.
Huang Z, Liu C, Zheng G, Zhang L, Zhong Q, Zhang Y et al. Articular Cartilage Regeneration via Induced Chondrocyte Autophagy by Sustained Release of Leptin Inhibitor from Thermo-Sensitive Hydrogel through STAT3/REDD1/mTORC1 Cascade. Adv Healthc Mater. 2023; 12(30): e2302181.
Huang Z, Liu C, Zheng G, Zhang L, Zhong Q, Zhang Y et al. Correction to "Articular Cartilage Regeneration via Induced Chondrocyte Autophagy by Sustained Release of Leptin Inhibitor from Thermo-Sensitive Hydrogel Through STAT3/REDD1/mTORC1 Cascade". Adv Healthc Mater. 2024; 13(7): e2304470.
Ito Y, Fukui M, Kanda M, Morishita K, Shoji Y, Kitao T et al. Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin andLeptin signaling in mice. J Pharmacol Sci. 2018; 137(1): 38-46.
Shelake G, Baviskar S, Panda AK, Solankure S, Pandey K, Chauthe S et al. Exploring the rare variants associated with Type 2 Diabetes Mellitus in Indian population and its disease-drug association studies: an in-silico approach. J Biomol Struct Dynamics. 2024; 42(12): 6307-22.
Itrat N, Nazir A, Saif K, Mushtaq Z, Nisa MU, Habib A, et al. Antidiabetic Flavonoids from Natural Sources. Adv Pharmacogn Phytochem Diabetes. 2024: 44.
Almathen F, Charruau P, Mohandesan E, Mwacharo JM, Orozco-terWengel P, Pitt D et al. Ancient and modern DNA reveal dynamics of domestication and cross-continental dispersal of the dromedary. Proc Natl Acad Sci U S A. 2016; 113(24): 6707-12.
Alrashdi I. Fog-based deep learning framework for real-time pandemic screening in smart cities from multi-site tomographies. BMC Med Imaging. 2024; 24(1): 123.
Amenu K, Agga GE, Kumbe A, Shibiru A, Desta H, Tiki W et al. MILK Symposium review: Community-tailored training to improve the knowledge, attitudes, and practices of women regarding hygienic milk production and handling in Borana pastoral area of southern Ethiopia. J Dairy Sci. 2020; 103(11): 9748-57.
Wang W, Melnikov F, Napoli J, Desai P. Advances in the Application of In Silico ADMET Models–An Industry Perspective. Computational Drug Discovery: Methods and Applications. 2024; 2: 495-535.
Ahmed MH, Karkush SI, Ali SA, Mohammed AA. Phytochemicals: a new arsenal in drug discovery. Int J Med Sci Dent Health. 2024; 10(01): 29-44.
Mohammed ED, Zhang Z, Tian W, Gangarapu V, Al-Gendy AA, Chen J et al. Modulation of IR as a therapeutic target to prevent NASH using NRF from Diceratella elliptica (DC.) jonsell. Strong Nrf2 and leptin inducer as well as NF-kB inhibitor. Phytomedicine. 2021; 80: 153388.
Pieterse C, Schutte R, Schutte AE. Leptin links with plasminogen activator inhibitor-1 in human obesity: the SABPA study. Hypertens Res. 2015; 38(7): 507-12.
Pena-Leon V, Perez-Lois R, Maria V, Prida E, Moreno DM, Fernø J et al. Novel mechanisms involved in leptin sensitization in obesity. Biochem Pharmacol. 2024: 116129.
Poulios E, Koukounari S, Psara E, Vasios GK, Sakarikou C, Giaginis C. Anti-obesity properties of phytochemicals: Highlighting their molecular mechanisms against obesity. Current Medicinal Chemistry. 2024; 31(1): 25-61.
Szekeres Z, Sandor B, Bognar Z, Ramadan FHJ, Palfi A, Bodis B et al. Clinical Study of Metabolic Parameters, Leptin and the SGLT2 Inhibitor Empagliflozin among Patients with Obesity and Type 2 Diabetes. Int J Mol Sci. 2023; 24(5).
Mandal AK, Sahoo A, Almalki WH, Almujri SS, Alhamyani A, Aodah A, et al. Phytoactives for Obesity Management: Integrating Nanomedicine for Its Effective Delivery. Nutrition Reviews. 2024: nuae136.
Md Mokhtar AH, Malik IA, Abd Aziz NAA, Almabhouh FA, Durairajanayagam D, Singh HJ. LY294002, a PI3K pathway inhibitor, prevents leptin-induced adverse effects on spermatozoa in Sprague-Dawley rats. Andrologia. 2019; 51(3): e13196.
Medeiros AF, Costa IS, Carvalho FMC, Kiyota S, Souza BBP, Sifuentes DN et al. Biochemical characterization of a Kunitz-type inhibitor from Tamarindus indica L. seeds and its efficacy in reducing plasma leptin in an experimental model of obesity. J Enzyme Inhib Med Chem. 2018; 33(1): 334-48.
Kawsar S, Munia NS, Saha S, Ozeki Y. In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Simulation Studies of Nucleoside Analogs for Drug Discovery-A Mini Review. Mini Rev Medicinal Chemistry. 2024; 24(11): 1070-88.
Muhammed MT, Aki-Yalcin E. Molecular docking: principles, advances, and its applications in drug discovery. Letters in Drug Design & Discovery. 2024; 21(3): 480-95.
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