Exploring Dual Agonists for PPARα/γ Receptors using Pharmacophore Modeling, Docking Analysis and Molecule Dynamics Simulation.

BACKGROUND: The Peroxisome Proliferator-Activated Receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits of insulin sensitization and lipid lowering into one drug, allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications. METHODS: The new PPARα/γ agonists were screened through virtual screening of pharmacophores and molecular dynamics simulations. First, in the article, the constructed pharmacophore was used to screen the Ligand Expo Components-pub database to obtain the common structural characteristics of representative PPARα/γ agonist ligands. Then, the accepted ligand structure was modified and replaced to obtain 12 new compounds. Using molecular docking, ADMET and molecular dynamics simulation methods to screen the designed 12 ligands, analyze their docking scores when they bind to the PPARα/γ dual targets, their stability and pharmacological properties when they bind to the PPARα/γ dual targets. RESULTS: We performed pharmacophore-based virtual screening for 22949 molecules in Ligand Expo Components-pub database. The compounds that were superior to the original ligand were performed structural analysis and modification, and a series of compounds with novel structures were designed. Using precise docking, ADMET prediction and molecular dynamics methods to screen and verify newly designed compounds, and the above compounds show higher docking scores and lower side effects. CONCLUSION: 9 new PPARα/γ agonists were obtained by pharmacophore modeling, docking analysis and molecular dynamics simulation.

Design, synthesis, biological evaluation and molecular dynamics simulation studies of imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 µM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

In-silico identification of peroxisome proliferator-activated receptor (PPAR)α/γ agonists from Ligand Expo Components database.

PPARα and PPARγ play important roles in regulating glucose and lipid metabolism. In recent years, the development of dual PPAR agonists has become a hot topic in the field of anti-diabetic medicinal chemistry. The dual PPARα/γ agonists can both improve metabolism and reduce side effects caused by single drugs, and has become a promising strategy for designing effective drugs for the treatment of type 2 diabetes. In this study, by means of virtual screening, molecular docking and ADMET prediction technology, a representative compound with higher docking score, lower toxicity than original ligands was gained from the Ligand Expo Components database. It was observed through MD simulation that the representative compound not only has the function of activating the PPARα target and the PPARγ target, but also show a more favorable binding mode when the representative compound binds to the two receptors compared to the original ligands. Our results provided an approach to rapidly find novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).This paper explores novel compounds targeting PPARα/γ dual agonists by using molecular docking, ADMET prediction, and molecular dynamics simulation methods. The specific flowchart is as follows: HighlightsThe results show that the skeleton of compound M80 is not only similar to Saroglitazar but also higher than that of Saroglitazar in activity.This study explained the binding modes of saroglitazar-PPARα/γ complexes and provided structure reference for the research and development of novel PPARα/γ dual agonists.

Virtual identification of novel peroxisome proliferator-activated receptor (PPAR) α/δ dual antagonist by 3D-QSAR, molecule docking, and molecule dynamics simulation.

The therapeutic potential of PPARs antagonists extends beyond diabetes. PPARs antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment. Thus, there is a strong need to develop a rational design strategy for creating PPARs antagonists. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of PPARα receptor (CoMFA-1, q 2 = 0.636, r 2 = 0.953; CoMSIA-1, q 2 = 0.779, r 2 = 0.999) and PPARδ receptor (CoMFA-2, q 2 = 0.624, r 2 = 0.906; CoMSIA-2, q 2 = 0.627, r 2 = 0.959) were successfully constructed using 35 triazolone ring derivatives. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking studies suggested that the hydrogen bonding, electrostatic and hydrophobic interactions all influenced the binding of receptor-ligand complex. Based on the information obtained above, we designed a series of compounds. The docking results were mutually validated with 3D-QSAR results. Three-dimensional-QSAR and absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions indicated that 19 newly designed compounds possessed excellent biological activity and physicochemical properties. In summary, this research could provide theoretical guidance for the structural optimization of novel PPARα and δ dual antagonists. Communicated by Ramaswamy H. Sarma.

Discovery of novel and highly selective PI3Kδ inhibitors based on the p110δ crystal structure.

Communicated by Ramaswamy H. Sarma.

Virtual identification of novel PPARα/γ dual agonists by 3D-QSAR, molecule docking and molecular dynamics studies.

Peroxisome proliferator-activated receptors (PPARs) are considered important targets for the treatment of Type 2 diabetes (T2DM). To accelerate the discovery of PPAR α/γ dual agonists, the comparative molecular field analysis (CoMFA) were performed for PPARα and PPARγ, respectively. Based on the molecular alignment, highly predictive CoMFA model for PPARα was obtained with a cross-validated q2 value of 0.741 and a conventional r2 of 0.975 in the non-cross-validated partial least-squares (PLS) analysis, while the CoMFA model for PPARγ with a better predictive ability was shown with q2 and r2 values of 0.557 and 0.996, respectively. Contour maps derived from the 3D-QSAR models provided information on main factors towards the activity. Then, we carried out structural optimization and designed several new compounds to improve the predicted biological activity. To investigate the binding modes of the predicted compounds in the active site of PPARα/γ, a molecular docking simulation was carried out. Molecular dynamic (MD) simulations indicated that the predicted ligands were stable in the active site of PPARα/γ. Therefore, combination of the CoMFA and structure-based drug design results could be used for further structural alteration and synthesis and development of novel and potent dual agonists. AbbreviationsDMdiabetes mellitusT2DMtype 2 diabetesPPARsperoxisome proliferator-activated receptorsLBDDligand based drug design3D-QSARthree-dimensional quantitative structure activity relationshipCoMFAcomparative molecular field analysisPLSpartial least squareLOOleave-one-outq2cross-validated correlation coefficientONCoptimal number of principal componentsr2non-cross-validated correlation coefficientSEEstandard error of estimateFthe Fischer ratior2predpredictive correlation coefficientDBDDNA binding domainMDmolecular dynamicsRMSDroot-mean-square deviationRMSFroot mean square fluctuationsCommunicated by Ramaswamy H. Sarma.

Identification of novel PPARα/γ dual agonists by pharmacophore screening, docking analysis, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field. In this paper, the compound CHEMBL230490 were gained from CHEMBL database, by means of complex-based pharmacophore (CBP) virtual screening, molecular docking, ADMET prediction and molecular dynamics (MD) simulations. The compound CHEMBL230490 not only displayed higher binding scores and better binding modes with the active site of PPARα a/γ, but also had more favorable the pharmacokinetic properties and toxicity evaluated by ADMET prediction. The representative compound CHEMBL230490 was performed to MDs for studying a stable binding conformation. The results indicated that the CHEMBL230490 might be a potential antidiabetic lead compound. The research provided a valuable approach in developing novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).

Identification of novel PI3Kδ inhibitors by docking, ADMET prediction and molecular dynamics simulations.

BACKGROUND: Phosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects. METHOD: Computer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor. RESULTS: Based on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: -12.175 kcal/mol, cdocker binding energy: -42.975 kcal/mol and ΔGbind value: -90.457 kcal/mol) and BAS 00227397 (Glide score: -10.988 kcal/mol, cdocker binding energy: -39.3376 kcal/mol and ΔGbind value: -81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand's behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket. CONCLUSION: Compound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.

Synthesis and biological evaluation of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1B.

α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α-glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides were synthesized and assayed for their α-glucosidase and PTP1B inhibitory activities, respectively. Compound 3l, exhibiting the most effective α-glucosidase inhibitory activity (IC50  = 10.96 µm (3l), IC50  = 51.32 µm (Acarbose), IC50  = 18.22 µm (Ursolic acid)) and potent PTP1B inhibitory activity (IC50  = 13.46 µm (3l), IC50  = 14.50 µm (Ursolic acid)), was identified as a novel dual inhibitor of α-glucosidase and PTP1B. Furthermore, 3l is a highly selective PTP1B inhibitor because no inhibition was showed by 3l at 100 µm against PTP-MEG2, TCPTP, SHP2, or SHP1. Subsequent kinetic analysis revealed 3l inhibited α-glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi-cation interactions all contributed to affinity between 3l and α-glucosidase/PTP1B.

Identification of novel PPARα/γ dual agonists by virtual screening, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ have been the most widely studied Peroxisome proliferator-activated receptor (PPAR) subtypes due to their important roles in regulating glucose, lipids, and cholesterol metabolism. By combining the lowering serum triglyceride levels benefit of PPARα agonists (such as fibrates) with the glycemic advantages of the PPARγ agonists (such as TZD), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence, has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of virtual screening, ADMET prediction and molecular dynamics (MD) simulations techniques, one compound-ASN15761007 with high binding score, low toxicity were gained. It was observed by MD simulations that ASN15761007 not only possessed the same function as AZ242 did in activating PPARα and BRL did in activating PPARγ, but also had more favorable conformation for binding to the two receptors. Our results provided an approach to rapidly produce novel PPARα/γ dual agonists which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.

Virtual identification of novel PPARα/γ dual agonists by scaffold hopping of saroglitazar.

The thiazolidinedione class PPARγ agonists as antidiabetic agents are restricted in clinical use because of the side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of side effects. The multi-target cooperative PPARα/γ dual agonist development is a hot topic in the antidiabetic medicinal chemistry field. Saroglitazar is the first approved PPARα/γ dual agonist, available in India for the treatment of diabetic dyslipidemia. It got rid of these side effects. With the aim of finding more protent PPARα/γ dual agonists, the scaffold hopping was used to replace α-o phenylpropionic acid skeleton of saroglitazar with L-tyrosine skeleton. Then, the structural modification was carried out designing 72 compounds. Considering the importance of chirality, opposite configuration of 72 compounds was also studied. 12 compounds with better -cdocker energy were screened by molecular docking. Subsequently, the pharmacokinetic properties and toxicity evaluated by ADMET prediction, 11 of them showed better properties. Comp#L-17-1 and comp#L-3-1 were regarded as representatives to study the binding stability by molecular dynamics (MD) simulations. The MD simulation results of comp#L-17-1-PPARs (α, γ) and comp#L-3-1-PPARs (α, γ) provided structure reference for the research and development of novel PPARα/γ dual agonists.

Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors.

PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 µM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules. The generated pharmacophore model revealed that the one RA, three Hyd, and two HBA features play an important role in binding to the active site of the target protein-PTP-MEG2. Docking simulation study indicated that 10a achieved its potency and specificity for PTP-MEG2 by targeting unique nearby peripheral binding pockets and the active site. The absorption, distribution, metabolism and excretion (ADME) predictions showed that the 11 compounds hold high potential to be novel lead compounds for targeting PTP-MEG2. Our findings here can provide a new strategy or useful insights for designing the effective PTP-MEG2 inhibitors.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists.

Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan.

It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (AT1R), but also exert stimulation in peroxisome proliferator-activated receptor γ (PPARγ) partial activation, among which telmisartan displays the best. Telmisartan has been tested as a bifunctional ligand with antihypertensive and hypoglycemic activity. Aiming at more potent leads with selective AT1R antagonism and PPARγ partial agonism, the three parts of telmisartan including the distal benzimidazole ring, the biphenyl moiety, and the carboxylic acid group experienced modification by core hopping method in our study. The central benzimidazole ring, however, remained intact considering its great affinity toward AT1R and PPARγ. We utilized computational techniques for the sake of details on the binding interactions and conformational stability. Standard precision docking analysis and absorption, distribution, metabolism, excretion, and toxicity prediction received 10 molecules with higher Glide scores, similar interactions, and improved pharmacokinetic profiles compared to telmisartan. Comp#91 with highest scores for AT1R (-11.92 kcal/mol) and PPARγ (-13.88 kcal/mol) exhibited excellent binding modes and pharmacokinetic parameters. Molecular dynamics trajectories on best docking pose of comp#91 confirmed the docking results and verified the conformational stability with both receptors throughout the course of 20-ns simulations. Thus, comp#91 could be identified as a promising lead in the development of dual AT1R antagonist and PPARγ partial agonist against hypertension and type 2 diabetes.

Multitargeted bioactive ligands for PPARs discovered in the last decade.

Type 2 diabetes took insulin resistance as the main clinical manifestation. PPARs have been reported to be the therapeutic targets of metabolic disorders, such as obesity, hypertension, diabetes, and cardiovascular disease. Previously, PPARγ agonist rosiglitazone was restricted in clinic due to cardiomyocytes infarction, weight gain, and other serious side-effects, which were mainly due to the single and selective PPARγ agonism. In recent years, multitarget-directed PPAR agonists with synergistic reaction as well as fewer side-effect have been the hot topic in designing promising agents. In this review, we updated and generalized the development of PPARγ partial agonists, PPARγ antagonists, PPARα/γ dual agonists, PPARδ partial agonists, PPARδ antagonists, PPARα/δ dual agonists, PPARγ/δ dual agonists, and PPARα/γ/δ pan-agonists published in recent decade. Most of these molecules were modified from known structures or came from high-throughput screening. Among these molecules, some were expected to be promising drugs against metabolic disorders, while others seemed to provide new insight for designing novel PPAR agents.

Identification of Novel PPARα/γ Dual Agonists by Virtual Screening of Specs Database.

Rosiglitazone was restricted clinically due to the side effects such as edema, weight gain and cardiac failure mainly attributing to the single and selective PPARγ activation. Nowadays, multi-targeted PPARs agonists remained to be a hot topic in the antidiabetic medicinal chemistry field. In this paper, the cooperative PPARα/γ dual agonists were screened from Specs database via the flow chart of docking, ADMET prediction and molecular dynamics (MD) simulations. Representative compounds ZINC36517927 and ZINC13573581 displayed higher binding scores, better pharmacokinetic profiles and were predicted to display the best binding affinity with PPARα/γ. Complex-based pharmacophore (CBP) models showed the key interactions in the PPARα/γ active sites. 20 ns simulations performed to the PPAR-ligand complexes indicated a stable binding conformation. This work provided an approach to identify novel high-efficiency PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).

Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.57-172 µM. A 3D-QSAR study using CoMFA and CoMSIA techniques was carried out to explore structure activity relationship of these molecules. The CoMSIA model was more predictive with q(2) = 0.777, r(2) = 0.999, SEE = 0.013 and r(2)pred = 0.836, while the CoMFA model gave q(2) = 0.543, r(2) = 0.998, SEE = 0.029 and r(2)pred = 0.754. The contour maps derived from the best CoMFA and CoMSIA models combined with docking analysis provided good insights into the structural features relevant to the bioactivity, and could be used in the molecular design of novel imidazolidine-2,4-dione derivatives.

Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.

The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.

Design novel inhibitors for treating cancer by targeting Cdc25B catalytic domain with de novo design.

The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.