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Exploration of stilbenoid trimers as potential inhibitors of sirtuin1 enzyme using a molecular Cite this: RSC Adv.,2021,11,19323 docking and molecular dynamics simulation approach†

Muhammad Ikhlas Abdjan,a Nanik Siti Aminah, *ab Imam Siswanto,a Alﬁnda Novi Kristanti,ab Yoshiaki Takayace and Muhammad Iqbal Choudhary de

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 A˚ at the receptor active site's coordinates. The molecular docking score uses a grid score functional (kcal mol1), 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 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. analysis because they had a lower grid score than the native ligand (1NS). Furthermore, prediction of binding free energy (kcal mol1) 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 Received 20th March 2021 enzyme. Additionally, the amino acid residues were responsible for the inhibition mechanism through Accepted 21st May 2021 hydrogen bond interactions at the molecular level, including ASP22, PHE91, PRO11, ILE165, ASP166, and DOI: 10.1039/d1ra02233d VAL230. The observations made in this study provide theoretical information for exploring the stilbenoid rsc.li/rsc-advances trimers as anticancer agents by targeting the SIRT1 enzyme. This article is licensed under a Introduction deacetylate other proteins to facilitate cell growth through cell cycle pathways, such as FOXO3a, RB1, KU70, and E2F1.10 Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. The enzyme sirtuin1 is present in the nucleus, and belongs to Besides, the activity of the SIRT1 enzyme can mediate cancer class III histone deacetylases (HDACs) which regulate multiple growth through the apoptotic pathway by inhibiting p53 biological processes.1,2 The enzyme sirtuin1 (SIRT1) is one of the activity.11 Therefore, studies regarding the inhibition of the isoforms of the sirtuin enzyme family (SIRT1–SIRT7), which has SIRT1 enzyme are promising as an inhibitory target in sup- become the center of attention due to its implications for pressing cancer growth. cancer.3–5 It is known that the overexpression of the SIRT1 Studies on the inhibition of the SIRT1 enzyme had reported – enzyme aﬀects cancer development, such as breast cancer,6,7 by several previous studies using in vitro approach.12 16 One of colon cancer,7 and prostate cancer.7,8 The nicotinamide adenine them was 4-(4-(2-[(methylsulfonyl)amino]ethyl)piperidin-1-yl) dinucleotide (NAD) deacetylase dependent plays an important thieno [3,2-d]pyrimidine-6-carboxamide had known can 9 16 role in regulating cellular stress responses. SIRT1 enzyme can inhibit the SIRT1 enzyme with IC50 value 4 nM. Additionally, stilbenoid derivatives showed SIRT1 (IC50 mM) enzyme inhibitory activity, such as stilbenoid dimer (()-ampelopsin F: 24.4 aDepartement of Chemistry, Faculty of Science and Technology, Universitas Airlangga, mM) and stilbenoid tetramer ((+)-vitisin A: 22.0 mM, ()-vitisin B: Surabaya 60115, Indonesia. E-mail: [email protected] 21.1 mM, (+)-hopeaphenol: 3.45 mM, ()-hopeaphenol: 18.1 mM, bBiotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga, and ()-isohopeaphenol: 21.6 mM).17 Indonesia Stilbenoid derivatives obtained from natural products are cFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya, 468- one of the solutions to get potential inhibitors against cancer.18 8503, Japan dH. E. J. Research Institute of Chemistry, International Center for Chemical and Stilbenoid derivatives are a class of polyphenol compounds 17,19 Biological Sciences, University of Karachi, Karachi-75270, Pakistan have known to inhibit the SIRT1 enzyme. Stilbenoid deriv- eAdjunct Professor Department of Chemistry, Faculty of Science and Technology, atives such as stilbenoid trimers isolated in the Dry- Universitas Airlangga, Komplek Kampus C UNAIR, Jl. Mulyorejo, Surabaya, Indonesia obalanops20,21 and Vitis labrusca22 plants, widely distributed in † Electronic supplementary information (ESI) available. See DOI: Indonesia and Malaysia. Structurally, the stilbenoid trimers 10.1039/d1ra02233d

consist of three resveratrol monomers, which are linked by labrusca (Fig. 1). The stilbenoid trimer compounds that were cyclic 2,3-dihydrofuran. Besides, the stilbenoid trimers have successfully isolated and characterized are ()-a-viniferin (TS1),22 three hydroxy (–OH) groups in each monomer.23 The presence of cis-diptoindonesin B (TS2),29 and trans-diptoindonesin B (TS3).29 this hydroxy group is expected to have a promising interaction The TS2 and TS3 compounds are new compounds that were with the amino acid residues at the active site of the SIRT1 successfully reported by previous research.29 enzyme in the form of a hydrogen bond donor (HBD). Geometry optimization of the stilbenoid trimers as a ligand The combination and integration of molecular docking and using the Semiempirical Quantum Method-Austin Model 1 molecular dynamic (MD) simulation is the main focus to study (SQM-AM1) to calculate the electrostatic potential (ESP) charges the potential of stilbenoid trimers as inhibitors of the SIRT1 using the Gaussian 16 package.30 The coordinates of the native enzyme. The structure-based approach has the advantage of ligand (PDB code: 1NS) and standard residue (receptor) were exploring the inhibitory mechanism through the interaction extracted from the crystal structure of SIRT1 (PDB code: 4ZZI) between ligand and receptor at the molecular level.24 Evaluation using Chimera version 1.13 package. Besides, missing residues of the interaction energy between ligand and receptor through and loop segments rebuilt using Modeller 9.21 package. The a combination of molecular docking and MD simulation are the AMBER FF14SB force eld and Austin Model 1-Bond Charge main parameters that are focused on this research. The grid Correction (AM1-BCC) had used to calculate ligand and receptor score functional has been reported to have the advantage of parameters such as bonded, non bonded, and charge. eﬃcient calculation in nding the coordinates of the receptor active site.25 Meanwhile, further evaluation about binding Molecular docking aﬃnity through the calculation of binding free energy using the Quantum Mechanics/Molecular Mechanics-generalized Born Molecular docking uses the performance of the Dock6 package. ˚ Surface Area (QM/MM-GBSA) method. The binding free energy The cluster sphere selection used a radius of 10.0 A from the calculation based on QM/MM requires a high cost and a long coordinates of the native ligand. The grid-box determination conducted using grid spacing 0.5 A˚ with a box size based on the

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. calculation time. However, calculation results can improve the prediction accuracy compared to conventional calculation selected cluster sphere. The minimization process at the (MM).26,27 It is expected that a structure-based approach by molecular docking stage needs to minimize the energy when considering the important parameters presented in this study the ligand docking process to the receptors. The type of – will help in understanding the inhibition mechanism of the conformation used in observing ligand receptor interactions is  stilbenoid trimers against the SIRT1 enzyme. exible conformation with energy calculations using a grid score functional. The validation process aims to nd out the best pose using the RMSD criterion # 2.0 A.˚ 31 This step aims to Methodology obtain the best possible native ligand coordinates as a reference ˚ This article is licensed under a with RMSD close to 0 A. Furthermore, footprint analysis had Ligand and receptor preparation done to see the residues responsible for the ligand–receptor The target protein used the NAD-dependent protein deacetylase interactions on the active site by comparing van der Waals sirtuin-1 (SIRT1) enzyme obtained from the Protein Data Bank energy (E ) and electrostatic energy (E ). This comparison Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. vdW ele (PDB code: 4ZZ1). The crystal structure of SIRT1 (PDB code: 4ZZ1) aims to see the diﬀerence between the EvdW and Eele of native has native ligands, namely 4-(4-(2-[(methylsulfonyl)amino]ethyl) ligand between the crystal structure (reference) and the piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide (PDB code: redocking result (pose). 1NS) at the active site's.28 The native ligand (1NS) was a reference in this study. Because it has known the 1NS ligand can inhibit the SIRT1 enzyme from previous research.16 Meanwhile, the ligand Molecular dynamics simulation candidates used in this study were stilbenoid trimer compounds Integration of the score function aims to obtain ligand coordi- obtained from the tree bark of Dryobalanops oblongifolia and Vitis nates from the docking results using the General AMBER Force

Fig. 1 Chemical structure of stilbenoid trimers isolated from the tree bark of Dryobalanops oblongifolia and Vitis labrusca, where the atomic label and ring region are marked.

Field (GAFF). Several AMBER18 tools such as antechamber and ns to produce trajectories for further analysis purposes. parmchk had used to generate ESP charges and missing ligand Trajectory analysis uses tools available in AMBER18, such as parameters. Topology preparation (ligand, receptor, complex, process_mdout.perl and cpptraj. Analysis of system stability, and solvated complex) using tleap. The solvent model used is such as total energy, temperature, density, pressure, and root- the TIP3P water solvent model with a minimum distance of 12 mean-square displacement (RMSD), was carried out for the A.˚ Then, the sodium ions (Na+) were randomly added to entire trajectory with a simulation time of 250 ns. Meanwhile, neutralize the simulated system. The process of system mini- further analysis needs such as root-mean-square uctuation mization goes through three stages of minimization: (i) mini- (RMSF), B-factor, atom contacts, the radius of gyration (RoG), mization of water molecules, (ii) minimization of complexes, solvent-accessible surface area (SASA), hydrogen bond, and ﬃ D and (iii) minimization of the entire system. The added hydrogen binding a nity ( Gbind) performed at the last 50 ns of the atoms and water molecules were minimized by 500 steps of trajectory. The calculation of binding free energy (DG) using the steepest descent and 3000 steps of conjugated gradient, while MMPBSA.py tools available in the AMBER18 package.32 The the rest of the atoms were restrained. This step aims to remove Quantum Mechanics/Molecular Mechanics-generalized Born poor atomic contacts. Then, the receptor and ligand were Surface Area (QM/MM-GBSA) method with quantum mechanics minimized by 500 steps of steepest descent and 3000 steps of theory used is the Austin Model 1 (AM1) method. Mathemati-

the conjugated gradient with the restrained solvent. Finally, the cally, binding free energy (DGbind) can be dened using eqn (1) entire system was fully minimized by the same procedure. The and (2). The determination of binding free energy using the heating stage of each system was gradually heated from 100 K to quantum mechanics (QM) method with the theoretical level of 310 K for 200 ps. The density (300 ps) stage and equilibrium AM1 Hamiltonian generate the calculation parameter of self D 33  (1000 ps) stage were performed with harmonic restrain of 30, consistent energy ( GSCF). Speci cally, the energy components 20, 10, and 5 kcal mol 1 A˚ 2. The entire system was simulated that aﬀect binding free energy can be detailed in the gas phase under the NPT (310 K and 1 atm) ensemble until reaching 250 (eqn (3)) and the solvation free energy (eqn (4)). The energy Creative Commons Attribution-NonCommercial 3.0 Unported Licence. This article is licensed under a Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM.

Fig. 2 Active site determination: (A) cluster sphere selected within radius 10 A˚ from the native ligand, (B) the ligand native is represented by a crystal conformation (cyan), a minimized conformation (blue), and a ﬂexible conformation (magenta), (C) the active site interaction between 1NS (ﬂexible conformation) and amino acid residues, (D) the interaction types shown in 2D-diagram.

component in the gas phase shows the energy component Table 1 Molecular docking validation of native ligand (1NS-4ZZI) using D ﬂexible conformation consisting of bonded energy ( Ebonded), van der Waals energy (DE ), and electrostatic energy (DE ).34 Meanwhile, the vdW ele Parameters Minimization Flexible solvation free energy is the total of generalized-Born models ele ˚ (DGsolv) and solvent-accessible surface area energy RMSD (A) 0.55 1.40 nonpolar 35 1 (DGsolv ). Grid score (kcal mol ) 75.72 79.56 1 EvdW (kcal mol ) 70.72 71.92 1 DG ¼ DG DG DG Eele (kcal mol ) 5.00 7.63 bind complex ( receptor + ligand) (1) 1 Eint (kcal mol ) 13.37 9.16

DGbind ¼ DGGas + DGSCF + DGsolv (2)

DGGas ¼ DEbonded + DEvdW + DEele (3) energy contribution in the interaction with the native ligands.37 ele nonpolar DGSolv ¼ DGsolv + DGsolv (4) The footprint analysis plays an important role in the docking validation process for the involvement of amino acid residues on the active site of the receptor (Fig. S1†). Overall, the footprint analysis on the native pose ligands of each amino acid residue

on the active site showed the energy value of the footprint (EvdW # 1 Results and discussion + Eele) 0 kcal mol . The analysis of amino acid residues having hydrogen bond interactions identied the EvdW + Eele Redocking: active site analysis values, such as PHE91: 8.45 kcal mol 1, ILE165: The active site determination of the SIRT1 enzyme plays 4.42 kcal mol 1, ASP166: 1.56 kcal mol 1, and VAL230: a crucial role in the success of molecular docking. The active 0.53 kcal mol 1, respectively. The coordinates of the receptor

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. site determination used the redocking method, which is the active sites have been successfully validated. It then meets the native ligand (1NS) against the receptor (SIRT1 enzyme) as criteria for the docking analysis stage of the stilbenoid trimers a reference. The coordinates obtained from the redocking as candidate ligand. process of the 1NS native ligand against the receptor can be used as a coordinate reference for the docking process of candidate stilbenoid trimers. The initial coordinates of the Molecular docking: stilbenoid trimers-SIRT1 enzyme native ligand on the active site selected based on the cluster ADMET predictions (absorption, distribution, metabolism, sphere within a radius of 10.0 A˚ (Fig. 2A). The native ligand that excretion, and toxicity) were performed using the pkCSM web- has docked in the sphere cluster is expected to provide good site service.38 ADMET analysis provides an important image in

This article is licensed under a coordinates according to the crystal structure's ligand reference predicting the activity of the candidate as a drug before using coordinates. The RMSD value expresses the native ligand molecular docking against the SIRT1 enzyme. Overall, the coordinate at the redocking stage. This value shows in two types results indicated that the stilbenoid trimers met the criteria for

Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. of conformation, which are minimization conformation and a good ADMET as a drug (Table S1†). Especially the toxicity exible conformation. The results show that the two confor- parameter, each candidate shows good suitability as a drug mation types' poses have good coordinates with the reference because it is non-toxic. ligands (Fig. 2B). The RMSD value between the reference ligand Molecular docking has been successfully implemented to and the ligand pose shows the diﬀerence in the initial coordi- study the interaction between the ligand candidate stilbenoid nates where the native ligand is located.36 Overall, the initial trimers and the SIRT1 enzyme as the target protein. The dock- coordinate determination showed a good 1NS native ligand ing algorithms were constructed to fast calculate the possible pose by meeting the criteria for an RMSD value # 2.0 A˚ (Table ligand conformation within the receptor active site.39 The 1). Furthermore, the binding energy analysis between the native process of docking the candidate ligand with SIRT1 enzyme was ligand (pose) and the receptor is calculated based on the grid carried out based on the initial coordinates obtained from the

score, which is the total energy of the van der Waals (EvdW) and redocking process using exible conformations. The results of

electrostatic (Eele) energy. The results show that the native the docking of candidate ligands with the receptor showed that ligand (pose) has a grid score of 79.56 kcal mol 1 (exible the TS2 and TS3 ligands had good potential to bind to the SIRT1 conformation). It will be used as comparison data with the enzyme because they had a lower grid score than the native candidate ligand. ligand (Fig. 3). On the other hand, the TS1 candidate shows less Other parameters measured in the redocking process are the good interaction because it has a larger grid score than the

interaction of amino acid residues with the native ligand. The native ligand. The van der Waals energy (EvdW) and electrostatic

number of amino acid residues responsible for the interaction energy (Eele) to the grid score of each ligand in the gas phase.

with the native ligand is ten amino acid residues (Fig. 2C). In Especially EvdW has a signicant contribution. In detail, the more detail, the amino acid residues PHE91, ILE165, ASP166, results of the docking energy components (kcal mol 1), such as  and VAL230 are the amino acids that have signi cant contri- TS1 (EvdW: 20.03, Eele: 6.80), TS2 (EvdW: 76.44, Eele: 11.32), butions to their interactions as hydrogen bonds (Fig. 2D). The and TS3 (EvdW: 74.51, Eele: 9.16). Thus, overall the molecular footprint analysis aimed to see each amino acid residue's docking results have good potential in interacting with the

19326 | RSC Adv.,2021,11,19323–19332 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Paper RSC Advances Creative Commons Attribution-NonCommercial 3.0 Unported Licence. This article is licensed under a Fig. 3 Molecular docking result of the candidate-receptor shows closer on the pocket area of the active site. Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. SIRT1 enzyme as an inhibitor: TS2> TS3> 1NS > TS1. Based on and LYS262 (region A: O24). The TS3 compound shows that four these considerations, candidate ligands with a grid score > 1NS amino acid residues are involved in the hydrogen bond inter- (pose) grid score were selected for further analysis at the action, such as LYS21 (region B: O12), ASP22 (region A: O25), molecular dynamics simulation. GLU26 (region C: O50), and LYS262 (region A: O25). It should be Further analysis of the interaction between amino acid noted that there are some differences in the C region confor- residues and candidate ligand on the active site aims to study mation for the cis (TS2) and trans (TS3) positions of the stilbe- the candidate ligand's inhibition mechanism against the SIRT1 noid trimers, which cause different interactions with the amino enzyme at the molecular level. The interactions between ligand acid residues. It can be seen that the cis position tends to bind and receptor affect the conformation changes of the complex with the VAL230 and GLU234 residues as hydrogen bond structure.40 These conformational changes can lead to target donors. Conversely, the trans-position avoids both residues and protein inhibition. The candidate ligands' molecular docking is more likely to interact with the GLU26 residue as a hydrogen results with the SIRT1 enzyme showed several types of interac- bond donor. There is a slight difference at the atomic level due tions with the amino acid residues that were on the receptor to differences in conformation in region A on the ASP22 and active site (Fig. S2†). The TS1 ligand shows that ve amino acid LYS262 residues. The interaction occurs at atoms O24 for the cis residues are responsible for hydrogen bonding, including position and O25 for the trans position with the ASP22 and ASP22 (region A: O48 and region B: O46), PRO111 (region C: LYS262 residues as hydrogen bond donors. This interaction is O51), GLN112 (region A: O50), VAL230 (region B: O49), LYS262 expected to provide an overview of the inhibition mechanism of (region B: O46). Meanwhile, the TS2 compound shows that the SIRT1 enzyme at the molecular level. For further analysis is eight amino acid residues are involved in the hydrogen bond to understand the interaction between the stilbenoid trimers interactions, such as LYS21 (region B: O12), ASP22 (region A: and the SIRT1 enzyme. The deeper study should be carried out O24), ASP90 (region B: O26), TYR98 (region B: O1), PRO111 using molecular dynamics simulation. (region B: O1), VAL320 (region C: O50), GLU234 (region C: O51),

System stability MD simulation analysis: exibility, compactness, atom The stability analysis of each system through several stages, contacts, and solvent accessibility such as minimization, heating, density, equilibrium, and Trajectories analysis in the last 50 ns used to calculate some production, was carried out for 250 ns simulation time. Several crucial parameters for each system. The root-mean-square parameters need to be validated to see the system stability, such uctuation (RMSF) and B-factor analysis aimed at looking for as total energy, temperature, density, pressure, and RMSD. the complex exibility.44 The TS2-SIRT1 showed lower uctua- Overall, some of the parameters analyzed, such as total energy tion than the Apo protein, 1NS-SIRT1, and TS3-SIRT1 (Fig. 5). It (kcal mol 1), temperature (K), density (g mL 1), and pressure indicates that the TS2 complex is more rigid because it has (bar), showed good stability with no signicant uctuation smaller mean RMSF (nm) and B-factor (nm 2) values compared (Fig. S3†). It should be noted, the average value of each system is to the Apo protein, 1NS-SIRT1, and TS3-SIRT1 (Table S2†). 1NS-SIRT1 (total energy: 147,170 799.27, temperature: These results show a good correlation with the RMSD of each 310.00 1.58, density: 1.00 0.00, and pressure: 0.36 complex, as indicated by the dominance of the TS2-SIRT1 110.17), TS2-SIRT1 (total energy: 146,966 803.55, tempera- complex stability compared to other (Fig. 4). Specically, the ture: 310.01 1.57, density: 1.00 0.00, and pressure: 0.65 uctuation occurs in the entire complex during the simulation 111.34), and TS3-SIRT1 (total energy: 146,936 801.78, time (200–250 ns). In particular, the loop region for APO temperature: 310.00 1.58, density: 1.00 0.00, and pressure: protein, 1NS-SIRT1, and TS3-SIRT1 have uctuation above 1.96 112.14). Meanwhile, the root-mean-square displacement RMSF: 1.0 nm and B-factor: 30 nm 2 (residues: 190–192, (RMSD) value of each system is the main parameter in assessing 212–223, and 323–328). the system stability for further analysis.41–43 The RMSD value Atom contacts identied that the interaction between ligand (nm) shows that each system has uctuation with its average and receptor occurred during the simulation time in the last 50 value of Apo protein: 0.27 0.04, 1NS-SIRT1: 0.31 0.04, TS2- ns trajectory (Fig. 6). The results showed that the 1NS ligand had SIRT1: 0.35 0.05, and TS3-SIRT1: 0.35 0.05. The TS2-SIRT1 more contact with the amino acid residues on the receptor's

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. system showed excellent stability compared to the Apo protein, active site than the TS2 and TS3 ligands (Table S2†). Addition- 1NS-SIRT1, and TS2-SIRT1 systems (Fig. 4). It shows that the ally, the radius of gyration (RoG) analysis is one of the param- uctuation occurred in the TS2-SIRT1 at the beginning of 70 ns eters for studying complex structure's compactness. The RoG and did not experience signicant uctuation until 250 ns. value can provide a good image of a stably folded structure or Signicant uctuation occurs in the Apo protein (90–105 ns), unfolded structure.45 It shows by looking at the RoG value of the 1NS-SIRT1 (90–105 ns), and TS3-SIRT1 (180–190 ns). The uc- Apo protein (without ligand) and 1NS-SIRT1 (with ligand) as the tuation occurs because there is a conformational change in the standard of comparison (Fig. 6). The results show that the mean complex structure during the simulation time. These confor- RoG values of the TS2-SIRT1 and TS3-SIRT1 complexes are mational changes occur in the protein and ligand structure. relatively identical and consistent with the mean RoG values of This article is licensed under a But, there were no signicant conformational changes in the 1NS-SIRT1 (Table S2†). Thus, these results identify the folded ligands. Additionally, the ligand coordinates of each complex TS2-SIRT1 and TS3-SIRT1 structures stably. are still on the active side (pocket) of the receptor. The analysis The solvent-accessible surface area (SASA) parameter aims to Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. process is carried out on the last 50 ns (200–250 ns) trajectory of determine how many water molecules (solvent) can access the each system for further analysis, considering that each system active site surface of the complex during the simulation.42 The has achieved good stability.

Fig. 4 Trajectories analysis: the root-mean-square displacement of Fig. 5 Flexibility analysis: the B-factor (top) and the root-mean-square each system plotted along the 250 ns of MD simulation. ﬂuctuation (bottom).

19328 | RSC Adv.,2021,11,19323–19332 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Paper RSC Advances Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Fig. 6 Trajectories analysis during the simulation over the last 50 ns: atom contacts within radius 3.5 A˚ (top), the radius of gyration (middle), and the solvent-accessible surface area (bottom).

results showed no signicant diﬀerence in the mean value of complex. The calculation of QM/MM-GBSA electrostatic term 2 SASA (nm ) between the Apo protein, 1NS-SIRT1, TS2-SIRT1, (DGSCF) using the semiempirical theory of Hamiltonian AM1 This article is licensed under a and TS3-SIRT1 (Table S2†). Furthermore, the TS2-SIRT1 shows shows an excellent contribution to the binding free energy. It that the surface-active site (radius 3.5 A˚ of the ligand) is more can be indicated by a more negative value in thermodynamic likely to be accessed by water molecules as a solvent than aspects.

Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. others. However, the overall analysis of the SASA values showed Each energy contribution provides the ligand-receptor good stability for each complex. It shows by low uctuation for binding affinity information expressed in terms of binding D the SASA value (Fig. 6). free energy ( Gbind). The TS2-SIRT1 and TS2-SIRT1 complexes show good binding affinity compared to INS-SIRT1 as the comparison standard. These results indicate that the stilbenoid Prediction of binding affinity trimers have an excellent potential in inhibiting the SIRT1 The stilbenoid trimers' susceptibility to the SIRT1 enzyme was enzyme through a strong binding on the active site of its inhi- performed using the QM/MM-GBSA method at 100 frames bition. To be more specic, the TS2 ligand has a lower DGbind extracted from the last 50 ns trajectories. The binding affinity prediction was calculated based on the contribution of ligands, Table 2 Binding free energy prediction calculated with the Quantum receptors, and complexes in the gas and solvated phases.46 The Mechanics/Molecular Mechanics-generalized Born Surface Area (QM/ calculation energy parameters generated using the MMPBSA.py MM-GBSA) method. Data are shown as mean standard error of tool contained in the AMBER18 package produce energy mean (SEM) components in detail (Table 2). The energy interaction in the Energy (kcal mol 1) 1NS-SIRT1 TS2-SIRT1 TS3-SIRT1 gas phase (DGgas) shows that the main contribution to the interaction between the receptor (SIRT1 enzyme) and the ligand DEvdW 56.88 0.26 69.96 0.30 68.61 0.35 is the van der Waals energy (DE ). It is indicated by a suitable D vdW Eele 0.25 0.00 0.14 0.00 0.15 0.00 contribution of the van der Waals energy, which is greater than DGgas 56.63 0.26 69.82 0.30 68.46 0.35 D the contribution of electrostatic energy (DEele). Meanwhile, the GSCF 46.08 0.48 49.62 0.45 42.69 0.44 D ele D Gsolv 77.42 0.49 70.10 0.41 76.83 0.31 solvated phase ( Gsolv) modeled using GB models shows the DGnonpolar 6.23 0.01 9.65 0.02 9.05 0.02 contribution of good binding energy in the solvent's polar free solv DGsolv 71.19 0.49 60.44 0.41 67.77 0.30 energy (DGele ). On the other hand, unsatisfactory results were solv DGbind 31.52 0.39 58.99 0.34 43.38 0.35 nonpolar noted on the solvent's nonpolar free energy (DGsolv ) for each

than the TS3, which allows the TS2 ligand as a SIRT1 inhibitor to have a better potency than the TS3 ligand. Overall, the binding free energy calculation results show the binding aﬃnity (kcal mol 1) of each complex: TS2 > TS3> 1NS. The results show a good correlation with the calculation of the grid score using molecular docking. Ligands that have low binding free energy are expected to bind with amino acid residues on the receptor active site, responsible for the activity of the SIRT1 enzyme. The strong binding aﬃnity between the ligand-receptors is expected to change the complex structure's conformation and block the active site of the SIRT1 enzyme. Thus, the SIRT1 enzyme becomes inactive in providing regulation of cellular stress responses through NAD-dependent protein deacetylase, which plays an important role in cancer development.47 The binding energy decomposition analysis aims to identify the contribution of residues that have good bonds with ligands. Its calculation performed using the MM-GBSA method (Fig. S4†). Residues that have good contribution energy criteria D residue # 1 48 are residues that have Gbind 1.0 kcal mol . The results show overall that 20 residues have good contribution energy criteria, such as HIE9, ILE12, ALA80, PHE91, ARG92, TYR98, PRO111, GLN112, PHE115, ASN164, ILE165, ASP166, HIE181,

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. VAL230, PHE231, PHE232, LEU236, LYS262, VAL263, and ARG264. Additionally, the 1NS-SIRT1 complex as a reference shows a good correlation between the energy decomposition and redocking result. Residues that correlate with bond contribution (MD simulation and docking) on the active site of the SIRT1 enzyme are PHE91, ILE165, ASP166, HIE181, VAL230, and PHE232 residues.

Hydrogen bonding analysis This article is licensed under a The hydrogen bond is a signicant interaction that contributes to a strong bond between ligand and receptor.48,49 It was

Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. recorded that the last 50 ns simulation time showed the number

Fig. 8 Visualization of hydrogen bond interaction between candidate and receptor on the active site. Hydrogen bond data are represented by a green line with the average value of distance in the angstroms unit (A).˚

of hydrogen bond (Fig. S5†) and the percentage of hydrogen bond occupation (Fig. 7) of each ligand with amino acid residues on the active site of the SIRT1 enzyme. However, the amount of hydrogen having good bonding criteria is expressed by the presentation of hydrogen occupation during the simulation time. In detail, the hydrogen bond of each complex is well recorded through the interactions at the atomic level (Fig. 8). The 1NS ligand shows that there are four amino acid residues involving ve hydrogen bonds: (i) O17/H–N (ILE165) at Fig. 7 Percentage of hydrogen bond over the last 50 ns of MD 52.32%, 2.83 A,˚ (ii) O (VAL230)/H–N3 at 52.28%, 2.84 A,˚ (iii) simulation.

OD2 (ASP166)/H–N16 at 46.44%, 2.92 A,˚ (iv) N19/H–N Acknowledgements (PHE91) at 34.6%, 3.04 A,˚ and (v) O17/H–N (ASP166) at ˚ 34.42%, 3.01 A. The hydrogen bond identication of the 1NS This study was supported by the research grant Program of ligand using the MD simulation showed a good correlation with “HIBAH RISET MANDAT KOLABORASI MITRA LUAR NEGERI” the molecular docking results as an initial reference (Fig. 2D). from Institute for Research and Community Service, Universitas Meanwhile, for each ligand candidate shows the hydrogen bond Airlangga. Contract Number: 800/UN3.15/PT/2021. of the ligand TS2: (i) O (VAL230)/H–O50 (region C) at 99.26%, 2.65 A˚ and (ii) O (PRO111)/H–O1 (region B) at 97.38%, 2.71 A.˚ References Hydrogen bond TS3: (i) OD2 (ASP22)/H–O24 (region A) at 63.60%, 2.68 A,˚ (ii) OD1 (ASP22)/H–O50 (region C) at 56.32%, 1 T. Liu, P. Y. Liu and G. M. Marshall, Cancer Res., 2009, 69, 2.65 A,˚ (iii) OD1(ASP22)/H–O24 (region A) at 25.16%, 2.67 A,˚ 1702–1705. and (iv) OD2 (ASP22)/H–O50 (region C) at 23.04%, 2.64 A.˚ 2 F. Yang, N. Zhao, D. Ge and Y. Chen, RSC Adv., 2019, 9, These results indicate that the TS2 ligand has a strong inter- 19571–19583. action with two amino acid residues (POR111 and VAL230) on 3 Z. Lin and D. Fang, Genes Cancer, 2013, 4,97–104. the active site of the SIRT1 enzyme. The TS2 ligand has 4N.Wossner,¨ Z. Alhalabi, J. Gonz´alez, S. Swyter, J. Gan, a hydrogen bond occupation $90%, which indicates the criteria K. Schmidtkunz, L. Zhang, A. Vaquero, H. Ovaa, O. Einsle, for a strong hydrogen bond.42 The TS3 ligand has four hydrogen W. Sippl and M. Jung, Front. Oncol., 2020, 10,1–15. bond interactions with one amino acid residue of ASP22 with 5 E. S. Hwang and S. B. Song, Cell. Mol. Life Sci., 2017, 74, a variation of occupation hydrogen bonds at diﬀerent atoms. 3347–3362. Hydrogen bond analysis shows a good evaluation of the TS2 6 V. Carafa, L. Altucci and A. Nebbioso, Front. Pharmacol., candidate ligands that have strong bond criteria. This result 2019, 9,1–14. shows a good correlation with the RMSD value of the TS2 7 C. X. Deng, Int. J. Biol. Sci., 2009, 5, 147–152.

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. complex (Fig. 4), which has good stability compared to the 1NS 8 L. Ruan, L. Wang, X. Wang, M. He and X. Yao, Oncotarget, and TS3 complexes. It is possible due to the inuence of the 2018, 9, 2002–2016. strong hydrogen bond possessed by the TS2 complex. Besides, 9 M. C. Vasquez and L. Tomanek, Comp. Biochem. Physiol., Part the hydrogen bond can be an important factor in inhibiting the A: Mol. Integr. Physiol., 2019, 236,1–11. SIRT1 enzyme. 10 E. Zhao, J. Hou, X. Ke, M. N. Abbas, S. Kausar, L. Zhang and H. Cui, Carbon, 2019, 11,1–22. 11 J. T. Lee and W. Gu, Genes Cancer, 2013, 4, 112–117. Conclusions 12 V. Heger, J. Tyni, A. Hunyadi, L. Horáková, M. Lahtela- Kakkonen and M. Rahnasto-Rilla, Biomed. Pharmacother., In this present study, a combination of molecular docking and This article is licensed under a 2019, 111, 1326–1333. molecular dynamics simulation was carried out to understand 13 M. V. B. Rao, D. SriLaxmi, S. V. Vardhini, V. R. Guttikonda, stilbenoid trimers' interaction as an inhibitor of the SIRT1 R. Kapavarapu and M. Pal, ChemistrySelect, 2020, 5, 14239– enzyme. The results of molecular docking using exible Open Access Article. Published on 27 May 2021. Downloaded 6/8/2021 2:45:02 AM. 14246. conformation show that the stilbenoid trimers interact well on 14 C. Sekhar, N. Kumar, V. Nallanchakravarthula, D. Nayakanti, the receptor's active site. The TS2 and TS3 ligands showed good R. Kapavarapu and M. Pal, J. Mol. Struct., 2021, 1240, 130541. interaction energy with the SIRT1 enzyme, indicated by the grid 15 D. S. Laxmi, S. V. Vardhini, V. R. Guttikonda, M. V. B. Rao score < grid score 1NS as the native ligand. Furthermore, the and M. Pal, Anti-Cancer Agents Med. Chem., 2020, 8, 932–940. binding affinity analysis using molecular dynamics simulation 16 J. S. Disch, G. Evindar, C. H. Chiu, C. A. Blum, H. Dai, L. Jin, with the QM/MM-GBSA approach shows that TS2 and TS3 E. Schuman, K. E. Lind, S. L. Belyanskaya, J. Deng, F. Coppo, ligands have DG < DG 1NS values. The hydrogen bond bind bind L. Aquilani, T. L. Graybill, J. W. Cuozzo, S. Lavu, C. Mao, interaction has an important role in the interaction of the stil- G. P. Vlasuk and R. B. Perni, J. Med. Chem., 2013, 56, 3666– benoid trimers with the amino acid residues on the active site of 3679. the SIRT1 receptor. The evaluation results using molecular 17 K. Hikita, N. Seto, Y. Takahashi, A. Nishigaki, Y. Suzuki, docking and molecular dynamics simulation showed that the T. Murata, A. Loisruangsin, N. S. Aminah, Y. Takaya, TS2 ligand has a stronger hydrogen bond (hydrogen bond M. Niwa and N. Kaneda, Nat. Prod. Commun., 2018, 13, occupation $90%) than the TS3. Additionally, the residues are 1531–1534. responsible for the hydrogen bond interaction on the TS2 are 18 M. H. Keylor, B. S. Matsuura and C. R. J. Stephenson, Chem. PRO111 and VAL230. Overall, the combination of molecular Rev., 2015, 115, 8976–9027. docking and molecular dynamics simulation processes evalu- 19 A. Loisruangsin, K. Hikita, N. Seto, M. Niwa, Y. Takaya and ated that the TS2 and TS3 ligands had promising potential as N. Kaneda, BioFactors, 2019, 45, 253–258. inhibitors of the SIRT1 enzyme. 20 Indriani, Y. Takaya, N. N. T. Puspaningsih and N. S. Aminah, Chem. Nat. Compd., 2017, 53, 559–561. Conflicts of interest 21 A. Wibowo, N. Ahmat, A. S. Hamzah, A. S. Suan, N. H. Ismail, R. Ahmad, F. M. Jaafar and H. Takayama, The authors declare no conict of interest. Fitoterapia, 2011, 82, 676–681.

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Themed collection 2021 RSC Advances HOT Article Collection

44 items

Review Article The phytochemistry, pharmacology and traditional medicinal use of Glechomae Herba – a systematic review

Liu Yang, Jiaxu Zhang, Senwang Zheng, Ajiao Hou, Song Wang, Huan Yu, Xuejiao Wang, Yingjie Xu, Haixue Kuang and Hai Jiang

Glechomae Herba is a Chinese herb, which has been used in China for thousands of years, mainly for the treatment of nephrolithiasis.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 27 May 2021 RSC Adv., 2021, 11, 19221-19237 https://doi.org/10.1039/D1RA01366A

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Paper

Transient release of radioactive iodine from the fission of UF4 in 2LiF–BeF2 salt Junxia Geng, Zhongqi Zhao, Zhiqiang Cheng, Wenxin Li, Qiang Dou, Haiying Fu, Jifeng Hu, Xiangzhou Cai, Jingen Chen and Qingnuan Li

The reaction between hot atoms of fission product iodine causes its partial release and is afected by the redox condition of FLiBe salt.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 28 Jun 2021 RSC Adv., 2021, 11, 22611-22617 https://doi.org/10.1039/D1RA03614A

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Paper In silico study of natural compounds from sesame against COVID-19 by targeting Mpro, PLpro and RdRp

Ahmed E. Allam, Yhiya Amen, Ahmed Ashour, Hamdy K. Assaf, Heba Ali Hassan, Islam M. Abdel-Rahman, Ahmed M. Sayed and Kuniyoshi Shimizu

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 24 Jun 2021 RSC Adv., 2021, 11, 22398-22408 https://doi.org/10.1039/D1RA03937G

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Paper Potential inhibitors for SARS-CoV-2 Mpro from marine compounds

Nguyen Minh Tam, Minh Quan Pham, Huy Truong Nguyen, Nam Dao Hong, Nguyen Khoa Hien, Duong Tuan Quang, Huong Thi Thu Phung and Son Tung Ngo

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 23 Jun 2021 RSC Adv., 2021, 11, 22206-22213 https://doi.org/10.1039/D1RA03852D

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Paper Photocatalytic and antibacterial activities of Tl–Hg–I nanocomposites: sonochemical synthesis and characterization

Elham Abkar, Mohammad Hassanpour, Omid Amiri, Mojgan Ghanbari and Masoud Salavati-Niasari

In this work, Tl4HgI6/HgI2 nanocomposites were synthesized by a rapid ultrasonic method. The photocatalytic properties of the nanocomposites were evaluated for the first time. Photocatalytic properties were performed for six industrial dyes.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 23 Jun 2021 RSC Adv., 2021, 11, 22238-22249 https://doi.org/10.1039/D1RA03666A

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Paper Natural steroid-based cationic copolymers cholesterol/diosgenin-r-PDMAEMAs and their pDNA nanoplexes: impact of steroid structures and hydrophobic/hydrophilic ratios on pDNA delivery

Zhao Wang, Jingjing Sun, Mingrui Li, Ting Luo, Yulin Shen, Amin Cao and Ruilong Sheng

Using natural-based lipids to construct biocompatible, controllable and eficient nanocarriers and elucidating their structure–function relationships, was regarded as an important area for creating sustainable biomaterials.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 01 Jun 2021 RSC Adv., 2021, 11, 19450-19460 https://doi.org/10.1039/D1RA00223F Download PDF Article HTML

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

Muhammad Ikhlas Abdjan, Nanik Siti Aminah, Imam Siswanto, Alfinda Novi Kristanti, Yoshiaki Takaya and Muhammad Iqbal Choudhary

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.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 27 May 2021 RSC Adv., 2021, 11, 19323-19332 https://doi.org/10.1039/D1RA02233D

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Paper A fluorine-18 labeled radiotracer for PET imaging of γ-glutamyltranspeptidase in living subjects

Dingyao Gao, Yinxing Miao, Siqin Ye, Chunmei Lu, Gaochao Lv, Ke Li, Chunjing Yu, Jianguo Lin and Ling Qiu

18 A radiotracer ([ F]GCPA)2 for sensitively and specifically detecting the expression level of γ- glutamyltranspeptidase in living subjects was reported. From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 24 May 2021 RSC Adv., 2021, 11, 18738-18747 https://doi.org/10.1039/D1RA01324F

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Paper Pd-catalyzed synthesis of 1-(hetero)aryl-2,2,2-trichloroethanols using chloral hydrate and (hetero)arylboroxines

Minori Shimizu, Yuta Okuda, Koki Toyoda, Ryo Akiyama, Hiraku Shinozaki and Tetsuya Yamamoto

N-heterocyclic carbene (NHC)-coordinated cyclometallated palladium complex (CYP) catalyzed (hetero)aryl addition of chloral hydrate using (hetero)arylboroxines, providing a new approach to 1- (hetero)aryl-2,2,2-trichloroethanols.

From the themed collection: 2021 RSC Advances HOT Article Collection

The article was first published on 18 May 2021 RSC Adv., 2021, 11, 17734-17739 https://doi.org/10.1039/D1RA02403E

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Paper Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2

Nguyen Minh Tam, Minh Quan Pham, Nguyen Xuan Ha, Pham Cam Nam and Huong Thi Thu Phung

Approved drugs predicted to interact with critical residues in the substrate-binding site of SARS-CoV- 2 Mpro can be promising inhibitors. Members' area (https://members.rsc.org/) | Support us (/support-us/)

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American Journal Expers Open

1 2 3 4 ACS Omega Frontiers in Chemistry Chemical Research in Progress in C Chinese Universities USA CHE CHE CHN 88% 81% 77% 7 similarity similarity similarity sim

SJR Total Documents

1.2The SJR is a size-independent prestige indicator that ranks 14kEvolution of the number of published documents. All types journals by their 'average prestige per article'. It is based on of documents are considered, including citable and non the1 idea that 'all citations are not created equal'. SJR is a citable documents. measure of scientifc infuence of journals that accounts 7k 0.8 for both the number of citations received by a journal and Year Documents the importance or prestige of the journals where such 2011 230 0.6 0 citations come from It measures the scientifc infuence of 2012 1720 the average article in a journal, it expresses how central to 2012 2014 2016 2018 2020 201320113289 2013 2015 2017 2019 the global scientifc discussion an average article of the 2014 8434

Total Cites Self-Cites Citations per document

120k Evolution of the total number of citations and journal's self- 4.5This indicator counts the number of citations received by citations received by a journal's published documents documents from a journal and divides them by the total during the three previous years. number of documents published in that journal. The chart Journal60k Self-citation is defned as the number of citation 3.6shows the evolution of the average number of times from a journal citing article to articles published by the documents published in a journal in the past two, three and same journal. four years have been cited in the current year. The two 2.7 0 years line is equivalent to journal impact factor ™ (Thomson Reuters) metric. Cites2011 Y2013ear Value2015 2017 2019 S lf Cit 2011 0 1.8 External Cites per Doc Cites per Doc Cites per document Year Value Cites / Doc. (4 years) 2011 0.000 0.9 E5volution of the number of total citation per document and Cites / Doc. (4 years) 2012 2.622 external citation per document (i.e. journal self-citations Cites / Doc. (4 years) 2013 3.899 removed) received by a journal's published documents Cites / Doc. (4 years) 2014 4.099 0 2.5during the three previous years. External citations are Cites / Doc. (4 years) 2015 3.687 Cites / Doc. (4 years) 2016 3.384 calculated by subtracting the number of self-citations from 2011 2013 2015 2017 2019 Cites / Doc. (4 years) 2017 3.175 the total number of citations received by the journal’s CitesCites / Doc./ Doc. (4 (4 y years)ears) 2018 3.276 documents.0 CitesCites / Doc./ Doc. (4 (3 y years)ears) 2019 3.260 2011 2013 2015 2017 2019 CitesCites / Doc./ Doc. (4 (2 y years)ears) 2020 3.356 Cit Y V l

% International Collaboration Citable documents Non-citable documents

International Collaboration accounts for the articles that Not every article in a journal is considered primary research have been produced by researchers from several countries. and therefore "citable", this chart shows the ratio of a The chart shows the ratio of a journal's documents signed journal's articles including substantial research (research articles, conference papers and reviews) in three year by researchers from more than one country; that is 40kwindows vs. those documents other than research articles, 28including more than one country address. reviews and conference papers.

24 Year International Collaboration 20kDocuments Year Value

Cited documents Uncited documents ← Show this widget in 40k Ratio of a journal's items, grouped in three years windows, your own website that have been cited at least once vs. those not cited during the following year. Just copy the code below 20k and paste within your html code: Documents Year Value