Inhibition of microsomal prostaglandin E
2
synthase-1 (mPGES-1) is promising for designing novel nonsteroidal anti-inflammatory drugs, as they lack side-effects associated with inhibition of ...cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Receiver operator characteristic (ROC) curves were used to evaluate the selectivity of each program. Furthermore, scoring power of Autodock4 and Autodock Vina was assessed by Pearson’s correlation coefficients. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (− 8.38 kcal/mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZINC001142847306) occupied the binding site of the substrate, prostaglandin H
2
(PGH
2
) and remained stable for 100 ns. Continuous hydrogen bonds and hydrophobic interactions with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.
A series of 3-aryl coumarin derivatives and 3-phenylazo-4-hydroxycoumarin were evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity by fluorometric enzymological ...assays. Among 21 coumarin derivatives, compound
21
(3-phenylazo-4-hydroxycoumarin) displayed a good inhibitory activity (0.12 ± 0.02 µM) and very high selectivity for MAO-B (SI > 833.33). The inhibition was determined as mixed-type and not time-dependent. Docking studies, molecular dynamics and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations were performed to elucidate
in vitro
results. Our results reveal that the insertion of an azo linker between coumarin and phenyl rings in 3-arylcoumarins enhances MAO-B selectivity enormously since such a linker leads to the perfect alignment of the coumarin ring in the aromatic cage and the phenyl ring in the entrance cavity of MAO-B active site. Hydrogen bond interactions with Cys172 in the active site entrance of MAO-B also contributes to the remarkably higher inhibitory activity and selectivity for MAO-B.
Display omitted
Development of new selective reversible monoamine oxidase (MAO) B inhibitors is still essential for the treatment of Alzheimer’s and Parkinson’s disease. Phthalonitrile compounds have ...been shown to display MAO inhibitory activity with MAO-B selectivity. In this study, we synthesized and evaluated the inhibitory activities of a new series of phthalonitrile compounds. Compound 3, 4 and 5 presented selective MAO-B inhibition, compound 5 being the most selective (75.16-fold). Additionally, molecular docking simulations were carried out. Investigation of binding modes of each compound with both isoforms were carried out to elaborate structure–activity relationships. Druglikeness was calculated for each compound, revealing that the lipophilicity of compound 5 (logP = 3.37) is optimal to cross membranes.
Display omitted
•Quaternary metallophthalocyanines bind to DNA with good docking scores.•Attractive charge and π-anion interactions largely account for the strong affinity.•Molegro appears to be more ...capable than Autodock Vina in distinguishing metals.•Incorporation of metal to phthalocyanines enhances DNA-binding.•Quaternary substituents improve DNA-binding ability of MPcs.
Phthalocyanines are considered as good DNA binders, which makes them promising anti-tumor drug leads. The purpose of this study is to investigate the interactions between DNA and quaternary metallophthalocyanine derivatives (Q-MPc) possessing varying metals (M = Zn, Ni, Cu, Fe, Mg and Ca) by molecular docking since there seems to be a lack of information in the literature regarding this issue. In this direction, Autodock Vina and Molegro Virtual Docker programs were employed. Autodock Vina results reveal that each Q-MPc derivative binds to DNA strongly with similar binding energies and almost identical binding modes. They bind to the grooves of DNA by constituting favorable interactions between phosphate groups of DNA and Q-MPcs. Although changing the metal has no significant effect on binding, presence of quaternary amine substituents increases the binding constant Kb by about 2-fold comparing to the core Pc (ZnPc). Contrary to Autodock Vina, the calculated Molegro Virtual Docker binding scores have been more diverse indicating that the scoring function of Molegro is better in differentiating these metals. Despite the fact that Molegro is superior to Autodock Vina in terms of metal characterization, Autodock Vina and Molegro exhibit similar binding sites for the studied metallophthalocyanines. We propose that Q-MPc derivatives designed in this study are promising anti-tumor lead compounds since they tightly bind to DNA with considerably high Kb values. Cationic substituents and presence of metal have both positive effects on DNA binding which is critical for designing DNA-active drugs. Additional calculations employing molecular dynamics (MD) simulations verified the stability of Q-MPc-DNA complexes which remained in contact after 20 ns via attractive interactions mainly between DNA backbone and the Pc metal center.
Cardiovascular diseases are one of the primary causes of deaths worldwide, and the development of atherosclerosis is closely related to hypercholesterolemia. As the reduction of the low‐density ...lipoprotein cholesterol level is critical for treating these diseases, the inhibition of 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase, which is essentially responsible for cholesterol biosynthesis, stands out as a key solution to lower plasma cholesterol levels. In this study, we synthesized several dihydroxycoumarins and investigated their antioxidant and in vitro HMG‐CoA reductase inhibitory effects. Furthermore, we carried out in silico studies and examined the quantum‐chemical properties of the coumarin derivatives. We also performed molecular docking experiments and analyzed the binding strength of each coumarin derivative. Our results revealed that compound IV displayed the highest HMG‐CoA reductase inhibitory activity (IC50 = 42.0 µM) in vitro. Cupric‐reducing antioxidant capacity and ferric‐reducing antioxidant power assays demonstrated that coumarin derivatives exhibit potent antioxidant activities. Additionally, a close relationship was found between the lowest unoccupied molecular orbital energy levels and the antioxidant activities.
Five dihydroxycoumarins were synthesized and investigated for their antioxidant and in vitro 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase inhibitory effects. The quantum‐chemical properties of the coumarin derivatives were explored and molecular docking was performed to determine the binding strength of each coumarin derivative. Compound IV displayed the highest HMG‐CoA reductase inhibitory activity, with IC50 = 42.0 µM.
inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is promising for designing novel non-steroidal anti-inflammatory drugs, as they lack side-effects associated with the inhibition of ...cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (-8.38 kcal/mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZiNC001142847306) occupied the binding site of the substrate, prostaglandin H2 (PGH2) and remained stable for 100 ns. Continuous hydrogen bonds with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.
