| Autor: |
Lim EQ; School of Science, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia., Ahemad N; School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia., Yap MKK; School of Science, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.; Tropical Medicine and Biology Multidisciplinary Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia. |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2023 Dec 15, pp. 1-15. Date of Electronic Publication: 2023 Dec 15. |
| DOI: |
10.1080/07391102.2023.2293275 |
| Abstrakt: |
Cobra venom cytotoxins (CTX) cause dermonecrosis in envenomed patients who suffered from limb amputations due to the limitation of serotherapy-based antivenoms. This study aimed to identify small molecule inhibitors against CTX. A structure-based high-throughput virtual screening (HTVS) was conducted based on a conserved CTX, using the Natural Product Activity and Species Source (NPASS) screening library. The hits were valerenic acid, 1-oxo-2H-isoquinoline-4-carboxylic acid, acenaphthene, and 5-bromopyrrole-2-carboxamide, which interacted with contemporary antivenom binding site A and functional loops I-III of CTX, respectively, in molecular docking studies. Furthermore, molecular dynamic simulations were performed along with analysis of ligand fitness through their pharmacophore and pharmacokinetics properties. The antagonist effects of these hits on CTX-induced cytotoxicity were examined in human keratinocytes (HaCaT). Despite having a low binding affinity (K D = 14.45 × 10 - 4 M), acenaphthene demonstrated a significant increase of cell viability at 6 h and 24 h in experimental envenomed HaCaT. It also demonstrated the highest neutralization potency against CTX with a median effective concentration (EC 50 ) of 0.05 mL/mg. Acenaphthene interacted with the functional loop II, which is the crucial cytotoxic site of CTX. It has an aromatic ring as its primary pharmacophoric feature, commonly used for rational drug design. In conclusion, acenaphthene could be a promising lead compound as a small molecule inhibitor.Communicated by Ramaswamy H. Sarma. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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