Anti-HHV-1 Mechanism and Pharmacokinetic Profile of Bioactive Compounds from Phaleria macrocarpa (Scheff.) Boerl Fruit

Nazlina Ibrahim; Poomangalaththazha Kuniyil  Safariya; Anis Sofea  Azman; Khairul Azreena   Bakar; Su Datt  Lam; Mahmud Y. Y.  Ismaeel

doi:10.55230/mabjournal.v55i3.3917

Authors

Nazlina Ibrahim
nazlina@ukm.edu.my
Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia
Poomangalaththazha Kuniyil Safariya Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia
Anis Sofea Azman Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia
Khairul Azreena Bakar Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
Su Datt Lam Department of Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia
Mahmud Y. Y. Ismaeel Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; Department of Medical Science, Abbs Community College, Hajjah, Yemen https://orcid.org/0000-0001-8059-7617

Keywords:

Antiviral activity, Human Herpes Virus Type-1 (HHV-1), Molecular Mechanistic Insight, Phaleria macrocarpa, Pharmacokinetic, compound

Abstract

This study reports on Phaleria macrocarpa fruit protein aqueous extract (PMFPAE) compounds, the mechanistic anti-human herpes virus type-1 (HHV-1) insights, and pharmacokinetic profiles. The mechanistic insight of PMFPAE treatment on the virus UL27 gene expression that encodes the viral attachment glycoprotein, gB, was determined to be downregulated at all replication phases, especially at 8 hr post-treatment, concurring with the late replication phase. Seven main water-soluble compounds in PMFPAE were identified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). These include organic acids (D-gluconic acid), xanthones (mangiferin, homomangiferin), and flavonoids (quercetin, myricetin 5-methyl ether, oroxylin A, and apigenin 7-glucuronide-4′-(6′‘-malonylglucoside)). All the compounds have drug-likeness properties according to Lipinski’s Rule of Five except for apigenin 7-glucuronide-4′-(6′‘-malonylglucoside). Except for quercetin and oroxylin A, the compounds have low gastrointestinal absorption, indicating low possibility for oral use. ProTox-II predicted D-Gluconic acid as the least toxic, and quercetin has the highest toxicity. CarcinoPredEL indicated none of the compounds to be carcinogenic. In molecular docking studies, two compounds, homomangiferin and apigenin 7-glucuronide-4’-(6′‘ malonylglucoside), showed strong binding affinity towards virus glycoprotein gB. Five compounds have strong binding towards the virus glycoprotein gD, including mangiferin, myricetin 5-methyl ether, homomangiferin, apigenin 7-glucuronide-4’-(6′‘ malonylglucoside), and quercetin. Homomangiferin can bind to both virus attachment glycoproteins gB and gD, with additional antioxidant and anti-inflammatory activities. Strong binding affinities of mangiferin and homomangiferin to site I (subdomain IIA) of human serum albumin (HSA) suggest effective compound transport within the bloodstream, enhancing their stability and half-life. In conclusion, PMFPAE consists of multifacet drug-like bioactive compounds that inhibit viral entry by binding to gB and gD and have antioxidant and anti-inflammatory activities. The predicted pharmacokinetic profile suggests that compounds of PMFPAE are more suitable for development as an anti-HHV topical agent due to the limited gastrointestinal absorption, toxicity of several key compounds, and limited binding to HSA.

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