Atreleuton

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.

It has been demonstrated that atherosclerotic disease progression is contingent upon chronic inflammation. The sequence of events leading up to plaque formation, instability, and eventual plaque rupture hinges upon the interaction of proinflammatory cytokines and fat deposition within the coronary vasculature. Over the past decade, a large body of evidence has demonstrated the efficacy of specific anti-inflammatory therapeutics in halting the progression of coronary artery disease. Despite this, these therapeutics have yet to be included in guideline-directed medical therapy regimens. This review will focus on several anti-inflammatories, which have been studied in the context of cardiovascular disease—colchicine, canakinumab, VIA-2291, and methotrexate, and will highlight the potential benefits majority hold in hindering atherosclerosis and cardiovascular disease progression. This holds especially true for individuals already on optimal medical therapy who continue to be at high risk for adverse cardiovascular events.