Narumol Phosrithong

Molecular docking study on anticancer activity of plant-derived natural products

A variety of compounds from plant sources have been reported to possess substantial anticancer properties; however, their modes of action have not been clearly defined. Selected plant-derived compounds that exhibit anticancer activity were subjected to docking simulations using AutoDock 3.0.5. To preliminarily investigate the potential molecular targets and to confirm the experimental activity testing for these anticancer compounds, the docking was performed using different enzymes and receptor proteins involved with cell cycle, cell growth, and DNA replication, i.e., cyclin-dependent protein kinase 2 (CDK-2), CDK-6, DNA topoisomerases I and II, B-cell lymphoma 2 (Bcl-2), vascular endothelial growth factor receptor 2 (VEGFR-2), and the telomere: G-quadruplexes. The docking results revealed that lupeol exhibited better binding interaction to CDK-2 and Bcl-2 than the known CDK-2 and Bcl-2 inhibitors. Epigallocatechin gallate (EGCG) was found to bind to CDK-6 with tighter interaction than several reported CDK-6 inhibitors. Flavopiridol, a synthetic flavonoid, was best bound to DNA topoisomerase I. Green tea catechin was best docked with topoisomerase II and VEGFR-2 and quercetin showed very good binding interaction with telomere: G-quadruplex. The experimental-derived inhibition constant (Ki) against Bcl-2 and Ki calculated from docking energy were well correlated. Therefore, the calculated Ki could be used as a preliminary tool for screening of Bcl-2 inhibitors before performing experimental activity assay.

In Vitro Antioxidant Activity Study of Novel Chromone Derivatives

Forty‐eight chromone derivatives were evaluated for their antioxidant activity using 2,2‐diphenyl‐1‐picrylhydrazyl free radical scavenging assay, ferrous ions (Fe2+) chelating activity test, total antioxidant activity test (Ferric thiocyanate and Thiobarbituric acid methods), and total reductive capability (potassium ferricyanide reduction). 7,8‐Dihydroxy‐2‐(3′‐trifluoromethylphenyl)‐3‐(3″‐trifluoromethylbenzoyl) chromone 32 showed stronger radical scavenging and metal chelating activities than butylated hydroxytoluene, vitamin E, and trolox. Chromone derivatives that exhibited good radical scavenging and metal chelating also displayed strong total antioxidant and reductive power activities. The results obtained from this study indicated that the synthesized chromone derivatives have remarkable antioxidant activity.

Ligand-based CoMFA and CoMSIA studies on chromone derivatives as radical scavengers

The antioxidant activity for a series of chromone compounds, evaluated by DPPH free radical scavenging assay, were subjected to 3D-QSAR studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). All 48 chromone derivatives were geometry optimized by AM1 and HF/6-31G(*) calculations. The CoMFA and CoMSIA results were compared between different alignment strategies. The best CoMFA model obtained from HF/6-31G(*) optimization with field fit alignment gave cross-validated r(2) (q(2))=0.821, noncross-validated r(2)=0.987, S=0.095, and F=388.255. The best CoMSIA model derived from AM1 optimized structures and superimposition alignment gave q(2)=0.876, noncross-validated r(2)=0.976, S=0.129, and F=208.073, including electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The contour maps provide the fruitful structure-radical scavenging activity relationships which are useful for designing new compounds with higher activity.

Docking study on anticancer activity of chromone derivatives

Several phenyl substituted chromones (also called flavonoids) have been reported to possess substantial anticancer properties; however, their modes of action have not been clearly defined. To preliminarily investigate the potential anticancer activity and mode of action of some synthetic chromone derivatives, the docking was performed using different enzymes and receptor proteins involved with cancer cell cycle, cell growth, and DNA replication, i.e., cyclin-dependent protein kinase-2 (CDK-2), CDK-6, DNA topoisomerases I and II, B-cell lymphoma-2 (Bcl-2), vascular endothelial growth factor receptor-2 (VEGFR-2), and the telomere: G-quadruplexes. The docking results revealed that chromone 32 exhibited better binding interactions to CDK-2 and Bcl-2 than the known CDK-2 and Bcl-2 inhibitors. Chromone 39 was found to bind to CDK-6 with tighter interaction than several reported CDK-6 inhibitors. Chromone 47 was best bound to both DNA topoisomerases I and II. Chromones 24 and 15 showed good binding interaction with VEGFR-2 and telomere: G-quadruplex, respectively. The inhibition constants (Ki) of each chromone compound against each target molecule were calculated. These Ki values could be used as a preliminary tool for screening specific inhibitors before performing experimental activity assay.

Biological activity evaluation and molecular docking study of chromone derivatives as cyclooxygenase-2 inhibitors

A series of chromone derivatives have been evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. The four most potent compounds, 48, 41, 39, and 35 displayed IC50 values of 3.30, 6.86, 7.36 and 7.46 µM, respectively. Compounds 35 and 38 showed higher selectivity for COX-2 (selectivity index, SI = 7.48 and 5.46, respectively) than celecoxib (SI = 4.17 in the same test) whereas compound 39 showed comparable selectivity (SI = 4.19) to celecoxib. The molecular volumes of compounds 35 (312.84 Å3) and 38 (314.18 Å3) were similar to celecoxib (299.28 Å3) but larger than ibuprofen (211.83 Å3). Docking results were in good agreement with the experimental biological data in terms of evaluation of binding energy and binding mode. Compounds 35, 38, and 39 had higher binding affinity against COX-2 (binding energy between −9.77 and −11.42 kcal/mole) than COX-1 (binding energy between −6.28 and −7.88 kcal/mole). These three chromone compounds also displayed active conformation in the same orientation as that of celecoxib. Thus, compounds in this series has the potential to be a new class of selective COX-2 inhibitor.

3D-QSAR studies on lipid peroxidation inhibitory activity of chromone derivatives

Lipid peroxidation has been implicated in disease states such as atherosclerosis, asthma, neurodegenerative disorders, Parkinson’s disease, cancer, etc. In this study, the anti-lipid peroxidation activity for a series of chromone compounds, evaluated in vitro by ferric thiocyanate and thiobarbituric acid assays, were subjected to three-dimensional quantitative structure-activity relationship studies using comparative molecular field analysis and comparative molecular similarity indices analysis. From ferric thiocyanate assay, the best comparative molecular field analysis and comparative molecular similarity indices analysis models gave cross-validated r2 (q2) = 0.563 and 0.593 and non cross-validated r2 = 0.974 and 0.929, respectively. The best comparative molecular field analysis and comparative molecular similarity indices analysis models derived from thiobarbituric acid assay gave q2 = 0.558 and 0.612, and non cross-validated r2 = 0.959 and 0.919, respectively. The generated hydrogen donor contour maps support the previously reported structure-activity relationship that the presence of a catechol moiety in ring A is essential for high potency.