Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis and biological activity

Abstract

Recent analyses have highlighted the promotion of cancer migration and invasion, mediated through HDAC via MMP-2 and MMP-9. Since both class 1 HDACs and MMP-2/9 are involved in the migration and invasion of cancer, an attempt has been taken to design dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping and molecular docking approaches. The designed molecules were synthesized and showed a range of inhibitory activity against different MMP subtypes. Most of these designed compounds were selective towards MMP-2 but less potent against anti-targets like MMP-8, -12, etc. The highly active MMP-2 inhibitors were also found to be active towards HDAC-8 but less potent against other class 1 HDACs (HDAC-1 and -2). Molecular dynamics simulations revealed that the designed compounds may be acting through a distinct mechanism of action in the 'acetate ion channel' of HDAC-8. Some potent dual MMP-2/HDAC-8 inhibitors were further explored for in vitro cellular assays against human lung carcinoma cell line A549. These analyses revealed that some of these dual inhibitors have considerable anti-migratory and anti-invasive properties. The work may help to obtain some useful dual inhibitors.

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

“…Additionally, more SAR studies are required to optimize the HDAC inhibitory activity. Also, Halder et al 117…”

“…Additionally, more SAR studies are required to optimize the HDAC inhibitory activity. Also, Halder et al . designed dual MMP‐2/HDAC‐8 inhibitors via developing pharmacophoric hypothesis based on the reported MPP‐2 inhibitors features, especially the glutamine‐derived MMP‐2 inhibitor (AS2‐5) 130 as a reference compound.…”

“…VDRs are responsible not only for calcium homeostasis but also they control cellular differentiation and proliferation. 105 The agonist ligand that turn on VDRs is the 1,25-dihydroxyvitamin D3 or 1,25D (117), which found recently to have powerful therapeutic potential in treatment of immune disorders and hyperproliferative disorders, such as psoriasis and cancer. 106 The main limitation for the use of 1,25D as an antiproliferative agent is the hypercalcemic adverse effects.…”

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

“…In a novel approach by Halder and co-workers, pharmacophore mapping and molecular docking techniques were employed to design a series of MMP2/HDAC8 dual inhibitors [ 119 ]. Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes responsible for the degradation of extracellular matrix proteins and who play crucial roles in physiological processes such as wound healing, tissue remodelling, angiogenesis and apoptosis [ 120 ].…”

Understanding Chemico‐Biological Interactions of Glutamate MMP‐2 Inhibitors through Rigorous Alignment‐Dependent 3D‐QSAR Analyses

“…None of these 3D‐QSAR models were developed comprising multiple types of alignment methods. In the current study, a variety of comprehensive alignment‐dependent (namely pharmacophore‐based, docking‐based and Open3DALIGN‐based alignment) 3D‐QSAR techniques have been performed to explore the structure‐property relationship of a series of glutamate‐based MMP‐2 inhibitors synthesized in the laboratory, for higher inhibitory activity. The MMP‐2 inhibitory activity (IC 50 in nM) of these compounds was transformed into the corresponding negative logarithmic scale [pIC 50 =log10 9 /IC 50 ] and was utilized for the development of 3D‐QSAR models.…”