J. Pharm. Pharmacogn. Res., vol. 13, Supplement 1, pp. S153-S165, Apr 2025.

DOI: https://doi.org/10.56499/jppres25.2327_13.s1.153

Original Article

Natural P2Y12 inhibitors as antiplatelet leads: A multi-tool in silico study

[Inhibidores naturales del P2Y12 como fármacos antiplaquetarios: Un estudio in silico con múltiples herramientas]

Abdulrahim A. Alzain^1ϯ*, Walaa Ibraheem^2ϯ, Fatima A. Elbadwi¹, Hagar M. Mohamed^3,4, Khaled M. Elamin⁵, Wadah Osman^6,7, Asmaa E. Sherif^6,8, Tariq M. Ajarba⁶, Ahmed Ashour^6,8, Reham M. Samra⁸, Gamal A. Mohamed⁹, Sabrin R.M. Ibrahim^10*

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan. 

²Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical & Health Science University, RAK, United Arab of Emirates.  

³Department of Medical Laboratory Analysis, College of Medical & Health Sciences, Liwa University, Abu Dhabi 41009, United Arab of Emirates.  

⁴Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt. 

⁵Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. 

⁶Department of Pharmacognosy, Faculty of Pharmacy, Prince Sattam bin Abdulaziz University, Al-kharj 11942, Saudi Arabia. 

⁷Department of Pharmacognosy, Faculty of Pharmacy, University of Khartoum, Khartoum, P.O. Box 1996, Sudan. 

⁸Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. 

⁹Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.  

¹⁰Department of Chemistry, Preparatory Year Program, Batterjee Medical College, Jeddah, 21442, Saudi Arabia.

^ϮAuthors contributed equally.

*E-mail: abdulrahim.altoam@uofg.edu.sd; abdulrahim.altoam@gmail.com (A.A.A.); sabrin.ibrahim@bmc.edu.sa (S.R.M.I.)

Abstract

Context: Uncontrolled platelet aggregation underlies thrombotic disorders and remains a major contributor to cardiovascular mortality. The platelet-specific P2Y₁₂ receptor is a validated target for antithrombotic therapy.

Aims: To identify natural P2Y₁₂ antagonists via an integrated in silico workflow.

Methods: Pharmacophore modeling (AAARR hypothesis), virtual screening of 449,008 SN3 natural compounds, Glide docking (HTVS→SP→XP), MM-GBSA rescoring, and 100 ns molecular dynamics simulations were employed.

Results: Three tannin derivatives (SN0208535, SN0257464, SN0084030) exhibited superior XP docking scores (≤ –15.0 kcal/mol), favorable MM-GBSA energies (≤ –84 kcal/mol), and stable binding throughout MD (RMSD ≤ 2.5 Å).

Conclusions: These compounds have promising potential for further development as new antiplatelet candidates.

Keywords: cardiovascular diseases; E-pharmacophore modelling and screening; health and wellbeing; molecular dynamics; natural product; P2Y12.

Resumen

Contexto: La agregación plaquetaria incontrolada subyace a los trastornos trombóticos y sigue siendo un factor importante en la mortalidad cardiovascular. El receptor P2Y₁₂ específico de plaquetas es una diana validada para la terapia antitrombótica.

Objetivos: Identificar antagonistas naturales del P2Y₁₂ mediante un flujo de trabajo integrado in silico.

Métodos: Se emplearon modelado de farmacóforos (hipótesis AAARR), cribado virtual de 449.008 compuestos naturales de SN3, acoplamiento Glide (HTVS→SP→XP), repuntuación MM-GBSA y simulaciones de dinámica molecular de 100 ns.

Resultados: Tres derivados de tanino (SN0208535, SN0257464, SN0084030) mostraron puntuaciones de acoplamiento XP superiores (≤ –15,0 kcal/mol), energías MM-GBSA favorables (≤ –84 kcal/mol) y una unión estable a lo largo de la MD (RMSD ≤ 2,5 Å).

Conclusiones: Estos compuestos tienen un potencial prometedor para su desarrollo como nuevos candidatos antiplaquetarios.

Palabras Clave: dinámica molecular; enfermedades cardiovasculares; modelado y cribado de e-farmacóforos; salud y bienestar; producto natural; P2Y12.

 

https://jppres.com/jppres/pdf/vol13/jppres25.2327_13.s1.153.pdf

 

 

Citation Format: Alzain MA, Ibraheem W, Elbadwi FA, Mohamed HM, Elamin KM, Osman W, Sherif AE, Ajarba TM, Ashour A, Samra RM, Mohamed GA, Ibrahim SRM (2025) Natural P2Y12 inhibitors as antiplatelet leads: A multi-tool in silico study. J Pharm Pharmacogn Res 13(s1): S153–S165. https://doi.org/10.56499/jppres25.2327_13.s1.153

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