Drug Targets for Cardiovascular-Safe Anti-Inflammatory: In Silico Rational Drug Studies

Abstract

Cyclooxygenase-2 (COX-2) plays an important role in memory consolidation and synaptic activity, the most fundamental functions of the brain. It converts arachidonic acid to prostaglandin endoperoxide H2. In contrast, if over-expressed, it causes inflammation in response to cytokine, pro-inflammatory molecule, and growth factor. Anti-inflammatory agents, by allosteric or competitive inhibition of COX-2, alleviate the symptoms of inflammation. Coxib family drugs, particularly celecoxib, are the most famous anti-inflammatory agents available in the market showing significant inhibitory effect on COX-2 activity. Due to high cardiovascular risk of this drug group, recent researches are focused on the investigation of new safer drugs for anti-inflammatory diseases. Natural compounds, particularly, phytochemicals are found to be good candidates for drug designing and discovery. In the present study, we performed in silico studies to quantitatively scrutinize the molecular interaction of curcumin and its structural analogs with COX-2, COX-1, FXa and integrin αIIbβIII to investigate their therapeutic potential as a cardiovascular-safe anti-inflammatory medicine (CVSAIM). The results of both ADMET and docking study indicated that out of all the 39 compounds studied, caffeic acid had remarkable interaction with proteins involved in inflammatory response. It was also found to inhibit the proteins that are involved in thrombosis, thereby, having the potential to be developed as therapeutic agent.

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

“…(COX-1) and 2 (COX-2), coagulation factor Xa (FXa) and integrin αIIbβ3 proteins, which are directly or indirectly participants in the thrombosis pathways [103].…”

“…In vivo, it was shown that the caffeic acid reduces the plasma TNF-α, IL-6 and IL-8 in rats receiving a high-fructose diet by decreasing the oxidative stress due to restoring of the antioxidant enzymes concentration (SOD, catalase, GSH-Px, glutathione reductase and glucose 6-phosphate dehydrogenase) [102]. In a very interesting in silico study, the caffeic acid was identified as a potential therapeutic agent having anti-inflammatory potential due to its interactions with cyclooxygenase-1 (COX-1) and 2 (COX-2), coagulation factor Xa (FXa) and integrin αIIbβ3 proteins, which are directly or indirectly participants in the thrombosis pathways [103].…”

“…The clinical efficacy of curcumin could be improved by formulations that enhance its solubility and stability and diminish the first-pass metabolism. To that end, certain strategies have been elaborated, such as the development of curcumin-piperine complexes, curcumin nanoparticles, cyclodextrin inclusions, curcumin liposomes and curcumin phospholipids' complexes, part of these systems exhibiting a 100-fold increase of bioavailability relative to unformulated curcumin [46].(COX-1) and 2 (COX-2), coagulation factor Xa (FXa) and integrin αIIbβ3 proteins, which are directly or indirectly participants in the thrombosis pathways [103].Another molecular mechanism associated with the positive effects of caffeic acid in ameliorating the lipid metabolism and oxidative and inflammatory stress is the regulation of epigenetic factors, in particular, miRNAs. Murase et al showed that in vitro treatment of Hepa1-6 hepatocytes with coffee polyphenols significantly increased cellular miR-122 expression, and reduced sterol regulatory element-binding transcription factor 1c (SREBP-1c) expression [104].…”

New Anti-inflammatory Flavonol Glycosides from Lindera akoensis Hayata

“…Caffeic acid is an effective anti-inflammatory substance. According to the literature [35,36,37,38], it inhibits inflammatory responses in many ways, including nitric oxide (NO) produced by various induction pathways, therefore the anti-inflammatory evaluation in this work used caffeic acid as positive control. linderakoside F (1) showed in vitro anti-inflammatory activity since it decrease the LPS-stimulated production of nitrite in RAW264.7 cell, with the IC 50 value 36.3 ± 3.2 μM a lot better than caffeic acid (162.8 ± 5.6 μM), in addition, they have no obvious cytotoxicity at the concentration of the experiment (Figure 3).…”

Docking studies in targeting proteins involved in cardiovascular disorders using phytocompounds from Terminalia arjuna

“…Talapatra et al [43] reported that phytocompounds from Calotropis procera such as methyl myrisate (-3.0) and methyl behenate (-3.2), β-sitosterol (-5.6), uzarigenin (-5.5) and anthocyanins (-5.4) showed good binding with CRP receptors. Caffeic acid had remarkable interaction with proteins involved in inflammatory response (COX-2, COX-1, FXa and integrin αIIbβIII), thereby, having the potential to be developed as cardiovascular-safe anti-inflammatory medicine [44]. In the present study, we have selected 19 compounds reported from stem bark of T. arjuna against protein targets of various cardiovascular disease.…”