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<p>Rheumatoid arthritis (RA), is a chronic autoimmune inflammatory disease which is also hyperplastic of the synovial joint and destructive of the joints, and they do not have much to cure. The extracellular heparin sulfate-modifying enzyme sulfatase-2 (SULF2) has become an important regulator of important signaling cascades that are involved in the pathogenesis of RA such as TNF-alpha-mediated cascades. Recent reports show that SULF2 is greatly over-expressed in RA synovial tissues and regulates fibroblast activation, expression of adhesion molecules and pro-inflammatory chemokines, highlighting its treatment applicability. In this regard, the de novo approach to drug design utilizing fragments is one approach that has a promising future in identified selective small-molecule inhibitors of SULF2. Multi-level computational methodology, such as physicochemical analysis, secondary and tertiary structure analysis, active site predictions, and high-throughput fragment screening, have been combined in this work to identify a number of novel ligand candidates with good binding affinities and drug-like properties. The stability and efficacy of lead compounds, in particular, MET-TRP-F1, were confirmed by comprehensive in silico studies including molecular docking, molecular dynamics simulations, MMGBSA free energy computations and ADMET profiling. Simulations of more than 500 ns of molecular dynamics showed the ability to maintain protein-ligand stability, reduce conformational change at the binding sites, and maintain secondary structures, as well as maintain strong hydrogen bonding interactions and favorable torsional flexibility of ligand. Energetic studies revealed that there was strong binding free energy with substantial hydrogen bonding, hydrophobic interactions, and electrostatic interactions, which lead to binding specificity and potency. These computational findings suggest that the inhibition of SULF2 can be used to mitigate the effect of RA-induced inflammatory signaling, thus providing a new pharmacotherapeutic target. This paper deals with the current weaknesses in sulfatase targeting by using fragment de novo methods, coupled with dynamic simulations methods to overcome specificity and efficacy problems. These results present a theoretical basis on which SULF2 inhibitors can be experimentally validated and optimized to become a part of the therapeutic repertoire that can help in the treatment of RA and other inflammatory diseases.</p>

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Fragment-based de novo drug design targeting sulfatase-2 (SULF2) for therapeutic intervention in rheumatoid arthritis

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Nouman Ali,
  • Adeeba Ali,
  • Amna Saleem

摘要

Rheumatoid arthritis (RA), is a chronic autoimmune inflammatory disease which is also hyperplastic of the synovial joint and destructive of the joints, and they do not have much to cure. The extracellular heparin sulfate-modifying enzyme sulfatase-2 (SULF2) has become an important regulator of important signaling cascades that are involved in the pathogenesis of RA such as TNF-alpha-mediated cascades. Recent reports show that SULF2 is greatly over-expressed in RA synovial tissues and regulates fibroblast activation, expression of adhesion molecules and pro-inflammatory chemokines, highlighting its treatment applicability. In this regard, the de novo approach to drug design utilizing fragments is one approach that has a promising future in identified selective small-molecule inhibitors of SULF2. Multi-level computational methodology, such as physicochemical analysis, secondary and tertiary structure analysis, active site predictions, and high-throughput fragment screening, have been combined in this work to identify a number of novel ligand candidates with good binding affinities and drug-like properties. The stability and efficacy of lead compounds, in particular, MET-TRP-F1, were confirmed by comprehensive in silico studies including molecular docking, molecular dynamics simulations, MMGBSA free energy computations and ADMET profiling. Simulations of more than 500 ns of molecular dynamics showed the ability to maintain protein-ligand stability, reduce conformational change at the binding sites, and maintain secondary structures, as well as maintain strong hydrogen bonding interactions and favorable torsional flexibility of ligand. Energetic studies revealed that there was strong binding free energy with substantial hydrogen bonding, hydrophobic interactions, and electrostatic interactions, which lead to binding specificity and potency. These computational findings suggest that the inhibition of SULF2 can be used to mitigate the effect of RA-induced inflammatory signaling, thus providing a new pharmacotherapeutic target. This paper deals with the current weaknesses in sulfatase targeting by using fragment de novo methods, coupled with dynamic simulations methods to overcome specificity and efficacy problems. These results present a theoretical basis on which SULF2 inhibitors can be experimentally validated and optimized to become a part of the therapeutic repertoire that can help in the treatment of RA and other inflammatory diseases.