Computational and experimental investigation of Kaempferol and Quercetin as potential inhibitors of MMP1 in oral cancer

Oral Cancer (OC) remains the most frequently reported malignancy characterized by low survival-rate, attributing to the lack of effective therapeutic-targets. Activities of several proteases, particularly matrix metalloproteinase (MMPs), induce epidermal hyperplasia increasing susceptibility to tumorogenesis. Their dual-nature in disease, wide-substrate specificity, and compensatory machinery makes them challenging to target. MMPs inhibitors have faced consequential challenges in clinical-applications. Hence, present study aimed to identify natural inhibitors of MMPs to aid preventive measures against OC carcinogenesis and therapeutics. Current study analyzed gene-expression of MMP1, MMP3, and MMP10 in tissues of head and neck cancer and normal, suggesting MMP1 as potential target. Virtual screening was performed to identify potential natural inhibitor for MMP1 target. Molecular Dynamic simulations (MDS) supported the binding abilities of the prioritized compounds, and ADMET analysis showed promising pharmacokinetic and pharmacodynamics properties. Computational findings were validated using in-vitro analysis and MMPs gene expression was evaluated after treatment in Cal27 and NOE cell lines. The results showed significant overexpression of MMPs in tumor samples and were strongly associated with clinico-pathological characteristics. Virtual screening identified L-epicatechin, 3-O-Methylquercetin, Fisetin, Quercetin, and Kaempferol as potential MMP1 inhibitors with high binding-affinity. Further, Kaempferol and Quercetin showing stability, conformation, and intermolecular interactions through MDS were prioritized for in-vitro validation. Kaempferol and Quercetin exhibited anti-proliferative and anti-migratory effects on Cal27 cells in time- and dose-dependent manners. Impaired gene-expression of MMPs after the treatment suggested potential of these compounds in preventing tumor invasion and metastasis and highlighted them as therapeutic-agents for the treatment-strategies in OC.