Mude Lavanya, Jupudi Srikanth, Swaroop Akey Krishna, Tallapaneni Vyshnavi, Karri Veera Venkata Satyanarayana Reddy
Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India.
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India.
J Biomol Struct Dyn. 2024 Mar;42(5):2437-2448. doi: 10.1080/07391102.2023.2209666. Epub 2023 May 9.
Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a role in healing, including reducing inflammation, promoting fibroblast and keratinocyte migration, and modifying scar tissue. Due to their pleiotropic functions in the wound-healing process in diabetic wounds, MMPs constitute a significant cause of delayed wound closure. COX-2 inhibitors are proven to inhibit inflammation. The present study aims to repurpose celecoxib against MMP-2, MMP-8 and MMP-9 through approaches, such as molecular docking, molecular dynamics, and MMPB/SA analysis. We considered five selective COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib, rofecoxib and valdecoxib) for our study against MMPs. Based on molecular docking study and hydrogen bonding pattern, celecoxib in complex with three MMPs was further analyzed using 1 µs (1000 ns) molecular dynamics simulation and MMPB/SA techniques. These studies identified that celecoxib exhibited significant binding affinity -8.8, -7.9 and -8.3 kcal/mol, respectively, against MMP-2, MMP-8 and MMP-9. Celecoxib formed hydrogen bonding and hydrophobic (π-π) interactions with crucial substrate pocket amino acids, which may be accountable for their inhibitory nature. The MMPB/SA studies showed that electrostatic and van der Waal energy terms favoured the total free binding energy component, while polar solvation terms were highly disfavored. The analysis of the secondary structures showed that the celecoxib binding conformation maintains relatively stable along the simulation trajectories. These findings provide some key clues regarding the accommodation of celecoxib in the substrate binding S1' pocket and also provide structural insights and challenges in repurposing drugs as new MMP inhibitors with anti-inflammatory and anti-inflammatory wound-healing properties.Communicated by Ramaswamy H. Sarma.
基质金属蛋白酶（MMPs）是蛋白水解酶，在愈合过程中发挥作用，包括减轻炎症、促进成纤维细胞和角质形成细胞迁移以及改变瘢痕组织。由于它们在糖尿病伤口愈合过程中具有多效性功能，MMPs是伤口愈合延迟的重要原因。COX-2抑制剂已被证明可抑制炎症。本研究旨在通过分子对接、分子动力学和MMPB/SA分析等方法，将塞来昔布重新用于对抗MMP-2、MMP-8和MMP-9。我们研究了五种选择性COX-2抑制剂（塞来昔布、依托考昔、卢米考昔、罗非昔布和伐地考昔）对抗MMPs的作用。基于分子对接研究和氢键模式，使用1微秒（1000纳秒）的分子动力学模拟和MMPB/SA技术进一步分析了与三种MMPs结合的塞来昔布。这些研究表明，塞来昔布对MMP-2、MMP-8和MMP-9分别表现出显著的结合亲和力，分别为-8.8、-7.9和-8.3千卡/摩尔。塞来昔布与关键底物口袋氨基酸形成氢键和疏水（π-π）相互作用，这可能是其抑制性质的原因。MMPB/SA研究表明，静电能和范德华能项有利于总自由结合能成分，而极性溶剂化项则极不受欢迎。二级结构分析表明，塞来昔布的结合构象在模拟轨迹上保持相对稳定。这些发现为塞来昔布在底物结合S1'口袋中的容纳提供了一些关键线索，也为将药物重新用作具有抗炎和促进伤口愈合特性的新型MMP抑制剂提供了结构见解和挑战。由拉马斯瓦米·H·萨尔马传达。
