Sains Malaysiana 53(5)(2024): 983-994

http://doi.org/10.17576/jsm-2024-5305-01

Unlocking Therapeutic Potential: Identifying Small Molecule Inhibitors for SARS-COV-2 Variants' Main Protease (M^PRO) Through Molecular Docking Analysis

(Membuka Kunci Potensi Terapeutik: Mengenal Pasti Perencatan Molekul Kecil untuk Protease Utama (M^PRO) Varian SARS-COV-2 Melalui Analisis Dok Molekul)

CHONG YIE WOON^1,2& NURUL IZZA ISMAIL^1,*

¹School of Biological Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia

²BiologicalDepartment of Chemistry, University of California Riverside, CA, USA

Received: 3 November 2023/Accepted: 8 April 2024

ABSTRACT

Even with existing emergency drugs, the development of safer and more effective drugs for the treatment of COVID-19 still needs to continue. Virtual screening through a molecular docking approach is a powerful way to discover potential compounds for new drug discovery. In this study, we targeted SARS-CoV-2 wild-type major protease (M^Pro), beta, lambda and omicron variants, to conduct a virtual screening with a selection of 100 ligands from the PubChem database using AutoDock Vina software. Among the inhibitors that have been identified are ten compounds consisting of ergotamine, 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide], remetinostat, benzamidine, argifin, irinotecan, dihydroergotamine, telmisartan, bromocriptine, and cilengitide, which exhibited the highest binding affinity. Interaction analysis through BIOVIA Discovery Studio showed the binding and interaction modes between these inhibitors and M^Pro residues of the variant. This mainly refers to 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide] and remetinostat which consistently exhibit strong interactions with M^Pro variants. This research provides promising leads for the development of potential COVID-19 therapeutics. In summary, targeting conserved M^Pro with small molecule inhibitors provides a solid foundation for combating SARS-CoV-2 and its variants, holding promise for effective COVID-19 mitigation.

Keywords: COVID-19; molecular docking; M^Pro; remetinostat; 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide]

Abstrak

Walaupun dengan ubat kecemasan yang sedia ada, pembangunan ubat yang lebih selamat dan berkesan untuk rawatan COVID-19 masih perlu diteruskan. Penyaringan maya melalui pendekatan dok molekul merupakan satu cara yang terbaik untuk penemuan sebatian yang berpotensi  bagi penemuan ubat baharu. Dalam kajian ini, kami menyasarkan protease utama (M^Pro) jenis liar SARS-CoV-2, beta, lambda dan varian omikron, untuk dijalankan saringan maya dengan pemilihan 100 ligan daripada pangkalan data PubChem menggunakan perisian AutoDock Vina. Antara perencat yang telah dikenal pasti adalah sepuluh sebatian terdiri daripada ergotamin, 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide], remetinostat, benzamidine, argifin, irinotecan, dihydroergotamine, telmisartan, bromocriptine dan cilengitide yang menunjukkan pertalian pengikatan tertinggi. Analisis interaksi melalui BIOVIA Discovery Studio mendedahkan mod pengikatan dan interaksi antara perencat ini serta sisa M^Pro bagi varian tersebut. Ini terutamanya merujuk kepada 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide] dan remetinostat yang secara tekalnya menunjukkan interaksi yang kuat dengan varian M^Pro. Penyelidikan ini memberikan petunjuk yang berpotensi untuk pembangunan terapeutik COVID-19. Ringkasnya, menyasarkan M^Pro yang dipelihara dengan perencat molekul kecil menyediakan asas yang kukuh untuk memerangi SARS-CoV-2 dan variannya, memegang janji untuk mitigasi COVID-19 yang berkesan.

Kata kunci: COVID-19; dok molekul; M^Pro; remetinostat; 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide]

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*Corresponding author; email: nurul.ismail@usm.my