Abstract
Matrix metalloproteinases 1 (MMP-1) energetically triggers the enzymatic proteolysis of extracellular matrix collagenase (ECM), resulting in progressive skin aging. Natural flavonoids are well known for their antioxidant properties and have been evaluated for inhibition of matrix metalloproteins in human. Recently, (-)-epicatechin and proanthocyanidin B2 were reported as essential flavanols from various natural reservoirs as potential anti-inflammatory and free radical scavengers. However, their molecular interactions and inhibitory potential against MMP-1 are not yet well studied. In this study, sequential absorption, distribution, metabolism, and excretion (ADME) profiling, quantum mechanics calculations, and molecular docking simulations by extra precision Glide protocol predicted the drug-likeness of (-)-epicatechin (−7.862 kcal/mol) and proanthocyanidin B2 (−8.145 kcal/mol) with the least reactivity and substantial binding affinity in the catalytic pocket of human MMP-1 by comparison to reference bioactive compound epigallocatechin gallate (−6.488 kcal/mol). These flavanols in docked complexes with MMP-1 were further studied by 500 ns molecular dynamics simulations that revealed substantial stability and intermolecular interactions, viz. hydrogen and ionic interactions, with essential residues, i.e., His218, Glu219, His222, and His228, in the active pocket of MMP-1. In addition, binding free energy calculations using the Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method suggested the significant role of Coulomb interactions and van der Waals forces in the stability of respective docked MMP-1-flavonol complexes by comparison to MMP-1-epigallocatechin gallate; these observations were further supported by MMP-1 inhibition assay using zymography. Altogether with computational and MMP-1–zymography results, our findings support (-)-epicatechin as a comparatively strong inhibitor of human MMP-1 with considerable drug-likeness against proanthocyanidin B2 in reference to epigallocatechin gallate.
Highlights
Skin, the outermost protective covering of the human body, is composed of a multilayered structure, i.e., oversimplified as an underlying matrix composed of a supporting dermis and a functional epithelium at the outer surface
Aging fibroblasts were reported to cause rapid synthesis and secretion of matrix metalloproteinases 1 and 3 (MMP-1 and MMP-3) to advance the skin aging process via degradation of the skin’s collagen matrix [6]. These MMPs, which belongs to the family of Ca2+-containing and Zn2+-dependent endopeptidases, are actively secreted by the keratinocytes and the dermal fibroblasts under the influence of multiple stimuli such as oxidative stress, Ultraviolet (UV) radiation, and cytokines [7,8]
Previous studies reported that oxidative stress produced in the epidermal cells by UV treatment activates the mitogen-activated protein kinase (MAPK) signaling pathway and the transcription factor activator protein 1 (AP-1) to promote skin aging by enhanced expression of Matrix metalloproteinases 1 (MMP-1) into the extracellular matrix (ECM) [13,14]
Summary
The outermost protective covering of the human body, is composed of a multilayered structure, i.e., oversimplified as an underlying matrix composed of a supporting dermis and a functional epithelium at the outer surface. The skin dermis is abundant with fibroblast cells that secrete structural components to support the extracellular matrix [2]. Aging fibroblasts were reported to cause rapid synthesis and secretion of matrix metalloproteinases 1 and 3 (MMP-1 and MMP-3) to advance the skin aging process via degradation of the skin’s collagen matrix [6]. These MMPs, which belongs to the family of Ca2+-containing and Zn2+-dependent endopeptidases, are actively secreted by the keratinocytes and the dermal fibroblasts under the influence of multiple stimuli such as oxidative stress, Ultraviolet (UV) radiation, and cytokines [7,8]. Several studies have suggested effective approaches to stimulate epidermal cell growth along with efficient remedies to suppress aging fibroblasts synthesizing and secreting matrix metalloproteinases (MMPs) [16]
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