Exploring the mechanism of action of spirooxindoles as a class of CDK2 inhibitors: a structure-based computational approach.

Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation. In this context, several studies have identified spirooxindoles as an effective class of CDK2 inhibitors. In the present study, three spirooxindoles (SOI1, SOI2, and SOI3) were studied to understand their inhibitory mechanism against CDK2 through a structure-based approach. Molecular docking and molecular dynamics (MD) simulations were performed to explore their interactions with CDK2 at the molecular level. The calculated binding free energy for the spirooxindole-based CDK2 inhibitors aligned well with experimental results regarding CDK2 inhibition. Energy decomposition (ED) analysis identified key binding residues, including I10, G11, T14, R36, F82, K89, L134, P155, T158, Y159, and T160, in the CDK2 active site and T-loop phosphorylation. Molecular mechanics (MM) energy was identified as the primary contributor to stabilizing inhibitor binding in the CDK2 protein structure. Furthermore, the analysis of binding affinity revealed that the inhibitor SOI1 binds more strongly to CDK2 compared to the other inhibitors under investigation. It demonstrated a robust interaction with the crucial residue T160 in the T-loop phosphorylation site, responsible for kinase activation. These insights into the inhibitory mechanism are anticipated to contribute to the development of potential CDK2 inhibitors using the spirooxindole scaffold.

In Vitro Assessment on Designing Novel Antibiofilms of Pseudomonas aeruginosa Using a Computational Approach.

An anti-biofilm that can inhibit the matrix of biofilm formation is necessary to prevent recurrent and chronic Pseudomonas aeruginosa infection. This study aimed to design compounds with a new mechanism through competitive inhibitory activity against phosphomannomutase/phosphoglucomutase (PMM/PGM), using in vitro assessment and a computational (in silico) approach. The active site of PMM/PGM was assessed through molecular redocking using L-tartaric acid as the native ligand and other small molecules, such as glucaric acid, D-sorbitol, and ascorbic acid. The docking program set the small molecules to the active site, showing a stable complex formation. Analysis of structural similarity, bioavailability, absorption, distribution, metabolism, excretion, and toxicity properties proved the potential application of ligands as an anti-biofilm. In vitro assessment with crystal violet showed that the ligands could reach up to 95.87% inhibition at different concentrations. The nitrocellulose membrane and scanning electron microscopic visualization showed that the untreated P. aeruginosa biofilm was denser than the ligand-treated biofilm.

A new labdane diterpenoid, in vitro and in silico cytotoxicity, and protease inhibitory effects of phytochemicals from Juniperus polycarposK. Koch leaves.

Cytotoxicity-guided purification of Juniperus polycarpos K. Koch leaves (Cupressaceae) led to the isolation of a new labdane diterpenoid, 3-(acetyloxy)-acetylisocupressic acid (1), together with isocupressic acid (2), 3,4-dimethoxycinnamoyl alcohol (3) and deoxypodophyllotoxin (4). The chemical structures of 1-4 were established by detailed 1D and 2D NMR, HRFAB-MS and LRESI-MS, as well as by comparing the spectral data with those reported in the literature. Compound 1 was ineffective against HepG2 cells and protease enzyme, while 2 showed potent cytotoxicity against HepG2 cells (IC50 of 3.73 µg/mL) compared to cisplatin (IC50 of 12.65 µg/mL). Computational analyses with CDK1 protein (a prominent protein in the cell cycle of HepG2 cells) revealed the binding affinity of 2 (-31.86 kcal/mol) was better than 1 (-19.70 kcal/mol) because the acetoxy groups did not allow binding deeply to the ATP binding site. Compounds 2 and 4 moderately inhibited the protease activity (IC50 = 52.7 and 63.0 µg/mL, respectively). Further in vitro and in vivo studies on the plant are strongly recommended.

Structure-based approach: molecular insight of pyranocumarins against α-glucosidase through computational studies.

α-glucosidase is an enzyme that catalyzes the release of α-glucose molecules through hydrolysis reactions. Regulation of this enzyme can increase sugar levels in type-2 diabetes mellitus (DM) patients. Pyranocoumarin derivatives have been identified as α-glucosidase inhibitors. Through an in silico approach, this work studied the inhibition of three pyranocoumarin compounds against the α-glucosidase at the molecular level. Molecular docking and molecular dynamics simulation were performed to understand the dynamics behavior of pyranocoumarin derivatives against α-glucosidase. The prediction of free binding energy (ΔG bind) using the Quantum Mechanics/Molecular Mechanics-Generalized Born (QM/MM-GBSA) approach for each system had the following results, PC1-α-Glu: -13.97 kcal mol-1, PC2-α-Glu: -3.69 kcal mol-1, and PC3-α-Glu: -13.68 kcal mol-1. The interaction energy of each system shows that the grid score, ΔG bind, and ΔG exp values had a similar correlation, that was PC1-α-Glu > PC3-α-Glu > PC2-α-Glu. Additionally, the decomposition energy analysis (ΔG residue bind) was carried out to find out the contribution of the key binding residue. The results showed that there were 15 key binding residues responsible for stabilizing pyranocumarin binding with criteria of ΔG residue bind < -1.00 kcal mol-1. The evaluation presented in this work could provide information on the molecular level about the inhibitory efficiency of pyranocoumarin derivatives against a-glucosidase enzyme based on computational studies.

3,4,3'-Tri-O-methylellagic acid as an anticancer agent: in vitro and in silico studies.

We report a natural product compound isolated from Syzygium polycephalum known as 3,4,3'-tri-O-methylellagic acid (T-EA) as a candidate drug for cancer treatment. The characterization of the isolated T-EA compound was carried out using various spectroscopic methods. The in vitro evaluation showcased the inhibition activity of T-EA towards the T47D and HeLa cell lines with EC50 values of 55.35 ± 6.28 µg mL-1 and 12.57 ± 2.22 µg mL-1, respectively. Meanwhile, the in silico evaluation aimed to understand the interaction of T-EA with enzymes responsible for cancer regulation at the molecular level by targeting the hindrance of cyclin-dependent kinase 9 (CDK9) and sirtuin 1 (SIRT1) enzymes. T-EA showed a binding free energy towards the SIRT1 protein of ΔG bind (MM-GBSA): -30.98 ± 0.25 kcal mol-1 and ΔG bind (MM-PBSA): -24.07 ± 0.30 kcal mol-1, while that of CDK9 was ΔG bind (MM-GBSA): -29.50 ± 0.22 kcal mol-1 and ΔG bind (MM-PBSA): -25.87 ± 0.40 kcal mol-1. The obtained results from this research could be considered as important information on 3,4,3'-tri-O-methylellagic acid as a drug to treat cervical and breast cancers.

Anticancer potential of ß-sitosterol and oleanolic acid as through inhibition of human estrogenic 17beta-hydroxysteroid dehydrogenase type-1 based on an in silico approach.

The human estrogenic enzyme 17beta-hydroxysteroid dehydrogenase type-1 (HSD17B1) provides biosynthesis regulation of active estrogen in stimulating the development of breast cancer through cell proliferation. The ß-sitosterol is classified as a steroid compound and is actually a type of triterpenoid compound that has a similar structure to a steroid. This similarity provides a great opportunity for the inhibitor candidate to bind to the HDS17B1 enzyme because of the template similarity on the active site. Several in silico approaches have been applied in this study to examine the potential of these two inhibitor candidates. Pharmacokinetic studies showed positive results by meeting several drug candidate criteria, such as drug-likeness, bioavailability, and ADMET properties. A combination of molecular docking and MD simulation showed good conformational interaction of the inhibitors and HSD17B1. Prediction of binding free energy (ΔG bind) using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) approach shows ΔG bind (kcal mol-1) of C1-HSD17B1: -49.31 ± 0.23 and C2-HSD17B1: -33.54 ± 0.34. Meanwhile, decomposition energy analysis (ΔG residue bind) suggested several key residues that were also responsible for the interaction with inhibitors, such as C1-HSD17B1 (six residues: Leu96, Leu149, Pro187, Met193, Val225, and Phe226) and C2-HSD17B1 (four residues: Ile14, Gly94, Pro187, and Val188). Hopefully, the obtained results from this research could be considered for the mechanistic inhibition of the HSDS17B1 enzyme at molecular and atomistic levels.

The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies.

An investigation has been carried out on natural products from dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CLpro) using an in silico approach. Inhibition of the 3CLpro enzyme is a promising target in stopping the replication of the SARS-CoV-2 virus through inhibition of the subsite binding pocket. The redocking process aims to determine the 3CLpro active sites. The redocking requirement showed a good pose with an RMSD value of 1.39 Å. The combination of molecular docking and MD simulation shows the results of DD13 as a candidate which had a good binding affinity (kcal mol-1) to inhibit the 3CLpro enzyme activity. Prediction of binding free energy (kcal mol-1) of DD13 using the Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB/GBSA) approach shows the results ΔG bind(MM-GBSA): -52.33 ± 0.34 and ΔG bind(MM-PBSA): -43.52 ± 0.42. The key residues responsible for the inhibition mechanism are Hie41, Ser46, Met49, Asn142, Cys145, Hie163, Met165, and Gln189. Additionally, pharmacokinetic prediction recommended that DD13 had promising criteria as a drug candidate. The results demonstrated in this study provide theoretical information to obtain a potential inhibitor against the SARS-CoV-2 main protease.

Exploration of stilbenoid trimers as potential inhibitors of sirtuin1 enzyme using a molecular docking and molecular dynamics simulation approach.

A combination of molecular docking and molecular dynamics simulation (250 ns) has been carried out to study the interaction of stilbenoid trimer compounds with the SIRT1 enzyme as the target protein. SIRT1 expression regulates cellular stress responses that lead to the development of cancer. Redocking showed a good native ligand pose with an RMSD value of 1.40 Å at the receptor active site's coordinates. The molecular docking score uses a grid score functional (kcal mol-1), which shows results of 1NS: 79.56, TS1: -26.83, TS2: -87.77, and TS3: -83.67. The TS2 and TS3 candidates were chosen for further analysis because they had a lower grid score than the native ligand (1NS). Furthermore, prediction of binding free energy (kcal mol-1) using the Quantum Mechanics/generalized Born Surface Area (QM/MM-GBSA) method shows the results of 1NS: -31.52 ± 0.39, TS2: -58.99 ± 0.34, and TS3: -43.38 ± 0.35. These results indicate that the TS2 and TS3 compounds have good potential as inhibitors of the SIRT1 enzyme. Additionally, the amino acid residues were responsible for the inhibition mechanism through hydrogen bond interactions at the molecular level, including ASP22, PHE91, PRO11, ILE165, ASP166, and VAL230. The observations made in this study provide theoretical information for exploring the stilbenoid trimers as anticancer agents by targeting the SIRT1 enzyme.

Potential of diterpene compounds as antivirals, a review.

Viruses cause widely transmitted diseases resulting in pandemic conditions. Currently, the world is being hit by the Covid-19 pandemic caused by the SAR-CoV-2 infection. Countries in the world are competing to develop antivirals to overcome this problem. Diterpene compounds derived from natural ingredients (plants, corals, algae, fungi, sponges) and synthesized products have potential as antivirals. This article summarizes the different types of diterpenes such as daphnane, tiglilane, kaurane, abietane, pimarane, labdane, dollabelane, jatrophane, dolastane, prenylated guaiane, tonantzitlolone, casbane, have antivirals activity such as targeting HIV, Coxsackie virus, herpes virus, hepatitis virus, influenza virus, Chikungunya virus, Zika virus, dengue virus, and SARS-CoV. Some compounds such as andrographolide and its derivatives show promising activity in inhibiting the influenza virus. Additionally, compounds such as pineolidic acid, forskolin, sugiol, and many other diterpene compounds showed anti-SAR-CoV activity. The diterpene compound class's high antivirals potential does not rule out the possibility that these compounds can also act as anti-SAR-CoV-2 drugs in the future.

In silico approach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway.

A combination of computational techniques has been carried out to predict the binding of nordentatin derivatives based on pyranocoumarin semi-synthesis with the target protein from the expression of the PDE4B gene. The inhibition of the cAMP pathway is the main target of anti-cancer drugs, which is responsible for uncontrolled cell division in cancer. Modeling was done using a combination of semi-empirical methods and the density functional theory (PM3-DFT/6-31G*/B3LYP) to obtain the optimal structure of a small ligand that could be modeled. Studies on the interaction of the ligands and amino acid residues on protein targets were carried out using a combination of molecular docking and molecular dynamic simulation. Molecular docking based on functional grid scores showed a very good native ligand pose with an RMSD of 0.93 Å in determining the initial coordinates of the ligand-receptor interactions. Furthermore, the amino acid residues responsible for interaction through H-bonds were Tyr103, His104, His177, Met217, and Gln313. The binding free energy (kcal mol-1) results of the candidates were PS-1 (-36.84 ± 0.31), PS-2 (-35.34 ± 0.28), PS-3 (-26.65 ± 0.30), PS-5 (-42.66 ± 0.26), PS-7 (-35.33 ± 0.23), and PS-9 (-32.57 ± 0.20), which are smaller than that of the native ligand Z72 (-24.20 ± 0.19), and thus these have good potential as drugs that can inhibit the cAMP pathway. These results provide theoretical information for the efficient inhibition of the cAMP pathway in the future.