Sains Malaysiana 54(1)(2025): 33-47

http://doi.org/10.17576/jsm-2025-5401-04

 

Pencirian Interaksi antara Labetalol Hidroklorida dengan Albumin Serum Manusia dan Glikoprotein Asid-α₁

(Characterization of the Interaction between Labetalol Hydrochloride with Human Serum Albumin and Acid Glycoprotein- α₁)

 

KHAIRUL AZREENA BAKAR¹, NG YAN HONG¹, MUHAMMAD FIRDAUS NAZRI¹, HANISAH FATINI MUHAMAD¹, THARISHINI SUBRAMANIAM¹, ROSHALINI UITHAYAKUMAR¹, AIDA NABILA ABDUL RAZAR¹ & SHEVIN RIZAL FEROZ^1,2,*

 

¹Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia
²Structural Biology and Protein Engineering Research Group, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

 

Received: 30 April 2024/Accepted: 18 September 2024

 

Abstrak

Labetalol hidroklorida (LAH) adalah sejenis dadah antihipertensi perencat α-β yang digunakan dalam rawatan hipertensi jangka panjang. Keberkesanan dadah ini bergantung kepada pengikatannya dengan protein plasma yang mempengaruhi sifat farmakokinetiknya. Walau bagaimanapun, terdapat jurang penyelidikan dari segi profil pengikatan LAH dengan albumin serum manusia (HSA) dan glikoprotein asid-α₁ (AAG), dua protein plasma manusia yang utama. Oleh itu, penyelidikan ini telah dijalankan untuk mencirikan interaksi antara LAH dengan HSA dan AAG menggunakan kaedah multispektroskopi, mikroskopi dan analisis struktur. Perubahan pada spektrum penyerapan UV protein menunjukkan berlakunya pembentukan kompleks protein–LAH. Analisis data spektroskopi pendarfluor menunjukkan bahawa interaksi protein–LAH mempunyai keafinan yang sederhana dan adalah berbalik. Namun, LAH didapati mempunyai afiniti pengikatan yang lebih tinggi dengan AAG berbanding HSA. Seterusnya, hasil analisis mikroskop daya atom menunjukkan perbezaan morfologi dan dimensi protein setelah mengikat dengan LAH. Berdasarkan analisis struktur LAH dan simulasi dok molekul, pembentukan kompleks LAH–protein melibatkan beberapa jenis ikatan intermolekul seperti ikatan hidrogen, daya hidrofobik dan pelbagai interaksi sistem-π. Hasil kajian sesaran dadah kompetitif merumuskan bahawa tapak II dan I HSA adalah tapak pengikatan primer dan sekunder bagi LAH, berpadanan dengan hasil analisis dok molekul. Maklumat daripada kajian ini boleh dimanfaatkan dalam penghasilan dadah terbitan LAH yang lebih cekap dan selamat.

 

Kata kunci: Albumin serum manusia; glikoprotein asid-α₁; hipertensi; interaksi dadah₋protein; labetalol hidroklorida

 

Abstract

Labetalol hydrochloride (LAH) is a α-β blocker used in the long term treatment of hypertension. The efficacy of this drug depends on its binding to plasma proteins, which influences its pharmacokinetic properties. However, there is a significant research gap in understanding the binding profile of LAH with the major human transport proteins, human serum albumin (HSA) and α₁-acid glycoprotein (AAG). Hence, this research was conducted to characterize the interaction of LAH with HSA and AAG using spectroscopic, microscopic, and structural analyses. Alterations in the UV absorption spectra of the proteins indicate the formation protein–LAH complexes. Fluorescence experiments showed moderate affinity and reversible binding between LAH and both proteins. However, LAH was found to interact more strongly with AAG compared to HSA. Furthermore, atomic force microscopic images showed differences in the morphology and dimensions of the proteins upon binding to LAH. Based on structural analysis of LAH and molecular docking results, the formation of the protein – LAH complexes involved various intermolecular forces including hydrogen bonds, hydrophobic interactions, and several π-system interactions. Competitive drug displacement results suggested sites II and I as the primary and secondary binding sites of LAH on HSA, respectively, in general agreement with the docking simulations. The present findings may be valuable in the development of more effective and safer derivatives of LAH.

 

Keywords: α₁-acid glycoprotein; drug–protein interaction; human serum albumin; hypertension; labetalol hydrochloride

 

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*Corresponding author; email: shevin@ukm.edu.my