Synthesis and Characterization of an All-Germanium Analogue of Cyclobutane-1,3-diyl.

A tetragermacyclobutane-1,3-diyl was prepared and structurally characterized via the reduction of chlorogermylene-coordinated germylgermylene with potassium graphite, which represents the first all-germanium analogue of cyclobutane-1,3-diyl. Single-crystal X-ray analysis of the tetragermacyclobutane-1,3-diyl disclosed that it adopts a planar-cis structure, which is different from those reported all-silicon cyclobutane-1,3-diyls. DFT calculations revealed that both the bulky substituents on the germanium atoms and the tethering of the amido groups are important for the planar cis-configuration of 5.

Screening and Activity Evaluation of Novel BCR-ABL/T315I Tyrosine Kinase Inhibitors.

INTRODUCTION: Chronic myeloid leukemia (CML) is a kind of malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. BCR-ABL fusion protein, found in more than 90% of patients, is a vital target for discovering anti-CML drugs. Up to date, imatinib is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved by the FDA for treating CML. However, the drug resistance problems appeared for many reasons, especially the T135I mutation, a "gatekeeper" of BCR-ABL. Currently, there is no long-term effective and low side effect drug in clinical. METHODS: This study intends to find novel TKIs targeting BCR-ABL with high inhibitory activity against T315I mutant protein by combining artificial intelligence technology and cell growth curve, cytotoxicity, flow cytometry and western blot experiments. RESULTS: The obtained compound was found to kill leukemia cells, which had good inhibitory efficacy in BaF3/T315I cells. Compound No 4 could induce cell cycle arrest, cause autophagy and apoptosis, and inhibit the phosphorylation of BCR-ABL tyrosine kinase, STAT5 and Crkl proteins. CONCLUSION: The results indicated that the screened compound could be used as a lead compound for further research to discover ideal chronic myeloid leukemia therapeutic drugs.

Structural Optimization of Cannabidiol as Multifunctional Cosmetic Raw Materials.

Cannabidiol (CBD), derived from the plant cannabis, can be used in the cosmetics industry for its antioxidant, anti-inflammatory, anti-wrinkle and whitening effects. However, CBD is purified from the hemp plant extract, its source is very limited and under strict control. So in this study, computational and experimental methods were combined to search for novel CBD substitutes with high biology potencies. The action mode between CBD and target protein cannabidiol receptor 1 was studied to find the key skeleton, which was used to virtually screen a natural products database to search for compounds with 70% similarity. The hit compounds with high docking scores were selected for the ABTS and DPPH free radical scavenging experiments for antioxidant evaluation. The effects on the expressions of nitric oxide (NO), interleukin-6 (IL-6), COX-2 and iNOS in RAW264.7 cell line were detected to demonstrate their anti-inflammatory abilities. The effect of anti-wrinkle ability were evaluated by detecting the extracellular matrix, such as collagen, elastin, fibronectin and reactive oxygen species (ROS) in HFF-1. The effects on melanin production and tyrosinase activity in Bb16F10 were also detected. As a result, two compounds were found to be superior to cannabidiol, in terms of antioxidant, anti-wrinkle and whitening efficacy with a lower cytotoxicity.

Sulfathiazole treats type 2 diabetes by restoring metabolism through activating CYP19A1.

Globally, diabetes mellitus has been a major epidemic bringing metabolic and endocrine disorders. Currently, 1 in 11 adults suffers from diabetes mellitus, among the patients >90% contract type 2 diabetes mellitus (T2DM). Therefore, it is urgent to develop new drugs that effectively prevent and treat type 2 diabetes through new targets. With high-throughput screening, we found that sulfathiazole decreased the blood glucose and improved glucose metabolism in T2DM mice. Notably, we discovered that sulfathiazole treated T2DM by activating CYP19A1 protein to synthesize estrogen. Collectively, sulfathiazole along with CYP19A1 target bring new promise for the better therapy of T2DM.

Lamivudine remedies alcoholism by activating acetaldehyde dehydrogenase.

Acute ethanol intoxication has become an alarming health problem. In the present study, we discover the beneficial effect of lamivudine on alcoholism in mice. Our results indicate that lamivudine decreases serum alcohol concentration dramatically, and potently activates acetaldehyde dehydrogenase (ALDH) to accelerate the conversion of acetaldehyde to acetic acid, which is finally metabolized by tricarboxylic acid cycle to be CO2 and H2O. Also, lamivudine significantly improves symptoms post drinking, such as prolonging alcohol tolerance time and shortening sobering time, as well as reducing the death rate. This work will provide new strategies for the prevention and treatment of acute alcoholism.

Recent Advances in the Chemistry of Heavier Group 14 Analogues of Carbonyls.

Heavier analogues of carbonyls, in the form of "R2 E=O" (E=Si, Ge, Sn, Pb), feature a high polar E=O double bond. In contrast to carbonyl compounds, heavier analogues are extremely unstable and prone to proceed head-to-tail oligomerization. Thus, the isolation of such species under ambient conditions is a challenging synthetic target in main group chemistry. In recent years, much progress has been achieved in the synthesis and isolation of a variety of Lewis base/acid, Lewis base-stabilized and even Lewis acid/base free heavier analogues. These compounds exhibit interesting reactivities, such as small molecule activation and metathesis reactions, indicating the potential of heavier analogues in synthetic chemistry. This review summarizes the recent achievements in the chemistry of Lewis base and/or acid stabilized heavier analogues of carbonyls, including synthetic approaches, structural parameters and reactivity of these isolable compounds.

The Discovery of Novel PGK1 Activators as Apoptotic Inhibiting and Neuroprotective Agents.

Stroke is the second leading cause of death worldwide and the leading cause of long-term disability that seriously endangers health and quality of human life. Tissue-type fibrinogen activator is currently the only drug approved by FDA for the treatment of ischemic stroke. Neuroprotection is theoretically a common strategy for the treatment of both ischemic and hemorrhagic stroke; therefore, the development of neuroprotective agent has been the focus of research. However, no ideal neuroprotective drug is clinically available. Phosphoglycerate kinase-1 (PGK1) activator has the effect of inhibiting apoptosis and protecting tissue damage, and therefore could be a potential neuroprotective agent. To obtain effective PGK1 activators, we virtually screened a large chemical database and their evaluated the efficacy by the Drosophila oxidative stress model, PGK1 enzymatic activity assay, and oxygen-glucose stripping reperfusion (OGD/R) model. The results showed that compounds 7979989, Z112553128 and AK-693/21087020 are potential PGK1 activators with protective effects against PQ-induced oxidative stress in the Drosophila model and could effectively ameliorate apoptosis induced by OGD/R-induced neuronal cell injury. Additionally, compounds 7979989 and Z112553128 are effective in alleviating LPS-induced cellular inflammation. This study indicated that these compounds are promising lead compounds that provide theoretical and material basis to the neuroprotective drug discovery.

Screening of activators of 2,3-diphosphoglycerate mutase from traditional Chinese herb medicines.

OBJECTIVE: To screen activators of 2,3-diphosphoglycerate (BPG) mutase (BPGM) from Chinese herb medicines, so as to improve the hypoxia tolerance of erythrocytes. METHODS: BPGM was used as the receptor and Chinese medicine ingredients database was used as the ligand in the study. After Lipinski rule of five screening, LibDock and CDOCKER docking were used for virtual screening. The effect of the screened compounds on the affinity of BPGM in erythrocytes was verified. Finally, the erythrocytes were incubated in vitro to establish the erythrocyte hypoxia model, and the effect of the compound on the activity of BPGM in the erythrocyte hypoxia model was verified. RESULTS: Ten compounds with highest binding affinity to BPGM were selected by LibDock and CDOCKER, and the cytoplasm protein was incubated with the ten compounds. Compared with blank control group, methyl rosmarinate group, dihydrocurcumin high dose group, octahydrocurcumin medium dose group and coniferyl ferulate high dose group were able to further activate the BPGM, significantly increase the levels of 2, 3-BPG in normal erythrocytes (all P<0.05); while the low dose of tetrahydrocurcumin, high dose and low dose of aurantiamide, hexahydrocurcumin and medium dose of N- (p-coumaroyl) serotonin had a tendency to increase the contents of 2,3-BPG in normal erythrocytes (all P>0.05). In the hypoxic red blood cells, the medium dose methyl rosmarinate, medium dose octahydrocurcumin, high dose hexahydrocurcumin and medium dose N-(p-coumaroyl) serotonin could significantly increase the contents of 2,3-BPG (all P<0.05). CONCLUSION: The methyl rosmarinate, octahydrocurcumin, hexahydrocurcumin and N-(p-coumaroyl) serotonin could activate BPGM and increase the contents of 2,3-BPG in hypoxic erythrocytes.

Antifungal sesquiterpenes with post-harvest anthracnose control effect on bananas from the fungus Fusarium lateritium.

To search for antifungal leads, the metabolites of an insect-derived fungus Fusarium lateritium ZMT01 were investigated, providing five sesquiterpenes (1-5), including new molecules microsphaeropsisins D and E (1 and 2). The evaluated antifungal activities in vitro which are higher than the positive control triadimefon include: 1 and 2 towards Fusarium oxysporum (MICs 50, 25 mg L-1; triadimefon 100 mg L-1); 1, 2, 4 and 5 towards Penicillium italicum (MICs 25, 12.5, 25, 25; triadimefon 50 mg L-1), 1, 2 and 4 towards Colletotrichum musae (MICs 25, 12.5, 25; triadimefon 80 mg L-1), 2 and 4 towards Fusarium graminearum (MICs 100, 100; triadimefon 150 mg L-1). The bioassay in vivo displayed that the banana anthracnose control effect of 2 (100 mg L-1) was also higher than that of triadimefon (Inhibition ratios 27.5 ± 2.5%, 55.3 ± 1.4%, 52.1 ± 1.3% for 2, 22.5 ± 2.1%, 47.2 ± 2.0%, 36.6 ± 2.2% for triadimefon at 4 d, 8 d and 12 d, respectively).[Formula: see text].

Anti-Oxidation and Anti-Inflammatory Potency Evaluation of Ferulic Acid Derivatives Obtained through Virtual Screening.

Various factors such as ultraviolet rays can cause a continuous threat to our skin, resulting in inflammation or oxidation problems. Ferulic acid (FA), with certain antioxidant and anti-inflammatory properties, is widely used in many cosmetics, even used to treat various diseases in the clinic. In this study, the FA structural skeleton was used to search for FA derivatives. Then, molecular docking, the rule of five, and Veber rules were performed to virtually screen compounds that can bind to proteins with a good drug likeness. DPPH and ABTS were used to evaluate their antioxidant potency and an MTT assay was employed to investigate the toxicities of the compounds, while Griess Reaction System and ELISA were used to judge the concentration variations of NO and different inflammatory factors (TNF-α, IL-1ß, and IL-6). Western blotting featured nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression levels. The trend of the intracellular changes of reactive oxygen species (ROS) was detected by the DCFH-DA method and fluorescence staining. As a result, we found that the ferulic acid derivative S-52372 not only had certain scavenging effects on free radicals in biochemical experiments, but also prevented inflammation and oxidative stress in LPS-stimulated RAW264.7 cells in the cellular environment; intracellular ROS and inflammatory mediators, including iNOS, COX-2, TNF-α, and IL-6, were also suppressed. In a computer prediction, S-52372 owned better water solubility and lower toxicity than FA. This compound deserves further research to find an ideal FA derivative.

New diphenyl ethers from a fungus Epicoccum sorghinum L28 and their antifungal activity against phytopathogens.

The strategy "IEMAHC" (Induction of Endophyte Metabolism by Adding Host Components) was applied to the fermentation of the endophytic fungus Epicoccum sorghinum L28 from Myoporum bontioides by introducing guaiol, an ingredient of M. bontioides, into the cultivation medium, which resulted in the purification of nine new diphenyl ethers, epicoccethers A-I (1-9). Their structures were determined by overall spectroscopic analysis. HPLC-MS analysis revealed that compounds 5-7 were products generated by induction of guaiol. Compounds 6 and 7 are the first members containing an ester moiety formed by the natural long-chain fatty acid and the hydroxyl group in the phenylmethanol unit of the diphenyl ether class. The antifungal activities of compounds 1, 2, and 4-7 against Fusarium oxysporum were 1, 1, 2, 1, 2 and 4 times as high as those of the positive control triadimefon, respectively. Compounds 4 and 5 showed 1.6 times the antifungal activities of triadimefon towards Colletotrichum musae.

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach.

Chronic myelogenous leukemia (CML) typically results from a reciprocal translocation between chromosomes 9 and 22 to produce the bcr-abl oncogene that when translated, yields the p210 BCR-ABL protein in more than 90% of all CML patients. This protein has constitutive tyrosine kinase activity that activates numerous downstream pathways that ultimately produces uncontrolled myeloid proliferation. Although the use of the BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib have increased the overall survival of CML patients, their use is limited by drug resistance and severe adverse effects. Therefore, there is the need to develop novel compounds that can overcome these problems that limit the use of these drugs. Therefore, in this study, we sought to find novel compounds using Hypogen and Hiphip pharmacophore models based on the structures of clinically approved BCR-ABL TKIs. We also used optimal pharmacophore models such as three-dimensional queries to screen the ZINC database to search for potential BCR-ABL inhibitors. The hit compounds were further screened using Lipinski's rule of five, ADMET and molecular docking, and the efficacy of the hit compounds was evaluated. Our in vitro results indicated that compound ZINC21710815 significantly inhibited the proliferation of K562, BaF3/WT, and BaF3/T315I leukemia cells by inducing cell cycle arrest. The compound ZINC21710815 decreased the expression of p-BCR-ABL, STAT5, and Crkl and produced apoptosis and autophagy. Our results suggest that ZINC21710815 may be a potential BCR-ABL inhibitor that should undergo in vivo evaluation.

Studying the Binding Modes of Novel 2-Aminopyridine Derivatives as Effective and Selective c-Met Kinase Type 1 Inhibitors Using Molecular Modeling Approaches.

The mesenchymal epithelial cell transforming factor c-Met, encoded by c-Met proto-oncogene and known as a high-affinity receptor for Hepatocyte Growth Factor (HGF), is one of the receptor tyrosine kinases (RTKs) members. The HGF/c-Met signaling pathway has close correlation with tumor growth, invasion and metastasis. Thus, c-Met kinase has emerged as a prominent therapeutic target for cancer drug discovery. Recently a series of novel 2-aminopyridine derivatives targeting c-Met kinase with high biological activity were reported. In this study, 3D quantitative structure-activity relationship (QSAR), molecular docking and molecular dynamics simulations (MD) were employed to research the binding modes of these inhibitors.The results show that both the atom-based and docking-based CoMFA (Q2 = 0.596, R2 = 0.950 in atom-based model and Q2 = 0.563, R2 = 0.985 in docking-based model) and CoMSIA (Q2 = 0.646, R2 = 0.931 in atom-based model and Q2 = 0.568, R2 = 0.983 in docking-based model) models own satisfactory performance with good reliabilities and powerful external predictabilities. Molecular docking study suggests that Tyr1230 and Arg1208 might be the key residues, and electrostatic and hydrogen bond interactions were shown to be vital to the activity, concordance with QSAR analysis. Then MD simulation was performed to further explore the binding mode of the most potent inhibitor. The obtained results provide important references for further rational design of c-Met Kinase type I inhibitors.

Virtual Screening and Bioactivity Evaluation of Novel Androgen Receptor Antagonists From Anti-PCa Traditional Chinese Medicine Prescriptions.

Prostate cancer (PCa), a type of malignancy that arises in the prostate gland, is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient treatment. Androgen receptor (AR) signaling pathway is necessary in the pathogenesis of prostate cancer, and there is a heightened interest in finding novel AR antagonists that target AR and its regulatory pathways. In our search for novel androgen receptor antagonists, we focus on the Traditional Chinese Medicine (TCM), which has been used for thousands of years to prove effective in the treatment of cancer. In this study, we collected 653 traditional Chinese medicine prescriptions that have certain therapeutic effect to prostate cancer, including the prescriptions and even the folk prescriptions. After summarizing the frequency of herbs and gathering the natural products contained in these prescriptions, we built a natural products database to do computer-aided virtual screening and drug-like evaluation to find potential AR antagonists. Totally 25 compounds were submitted to experimental biological activity tests. Through the MTT cell proliferation experiment, 5 chemicals were found to inhibit the proliferation of LNCaP cells in a concentration-dependent manner. Especially, MoL_11 was found to have good antagonistic activity and significantly inhibit fluorescence enzyme activity by the AR reporter gene experiment. Finally, the molecular dynamics simulation method was used to study the interaction between the most active compound MoL_11 and the wild-type and F876L mutant androgen receptor (WT/F876L AR), and it was found that F876L AR could not cause resistance to MoL_11.

Identification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is the second enzyme of the tyrosine catabolic pathway. Its physiological function is to catalyze the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, which displays different physiological effects in mammals and plants. Insights on the selective inhibition of human HPPD (hHPPD) by triketone inhibitors were furnished by the integrated application of molecular simulation and biological testing. The binding free energy of hHPPD and inhibitors was obtained through molecular dynamics (MD) simulations, and the result was in agreement with the inhibition experiment in vitro. The binding free energy contribution demonstrated that the formation of hHPPD-inhibitor complexes was mainly driven by van der Waals energy. Ser226, Asn241, Gln265, Phe336, Phe359 and Phe364 made great contributions to binding affinities of all the systems. Among the residues involved in the interaction between nitisinone (NTBC) and hHPPD, Tyr221 and Leu224, whose mutation into Ala caused significant decrease of NTBC binding ability, were two key residues in determining the selective binding affinity of inhibitor and hHPPD. This work provides valuable theoretical basis for rational design of highly selective inhibitors targeting hHPPD.

Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the µ-Opioid Receptor Upon Activation.

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the µ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros-Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR-ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

Combined 3D-quantitative structure-activity relationships and topomer technology-based molecular design of human 4-hydroxyphenylpyruvate dioxygenase inhibitors.

Aim: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as an important target against tyrosinemia type I. This paper aimed to explore the structure-activity relationship of HPPD inhibitors with pyrazole scaffolds and to design novel HPPD inhibitors. Methodology & results: The best 3D-quantitative structure-activity relationships model was established by two different strategies based on 40 pyrazole scaffold-based analogs. Screening of molecular fragments by topomer technology, combined with molecular docking, 14 structures were identified for potential human HPPD inhibitory activity. Molecular dynamics results demonstrated that all the compounds obtained bound to the enzyme and possessed a satisfactory binding free energy. Conclusion: The quantitative structure-activity relationship of HPPD inhibitors of pyrazole scaffolds was clarified and 14 original structures with potential human HPPD inhibitory activity were obtained.

CoMPARA: Collaborative Modeling Project for Androgen Receptor Activity.

BACKGROUND: Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) in vitro approaches and computational modeling. OBJECTIVES: In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP). METHODS: The CoMPARA list of screened chemicals built on CERAPP's list of 32,464 chemicals to include additional chemicals of interest, as well as simulated ToxCast™ metabolites, totaling 55,450 chemical structures. Computational toxicology scientists from 25 international groups contributed 91 predictive models for binding, agonist, and antagonist activity predictions. Models were underpinned by a common training set of 1,746 chemicals compiled from a combined data set of 11 ToxCast™/Tox21 HTS in vitro assays. RESULTS: The resulting models were evaluated using curated literature data extracted from different sources. To overcome the limitations of single-model approaches, CoMPARA predictions were combined into consensus models that provided averaged predictive accuracy of approximately 80% for the evaluation set. DISCUSSION: The strengths and limitations of the consensus predictions were discussed with example chemicals; then, the models were implemented into the free and open-source OPERA application to enable screening of new chemicals with a defined applicability domain and accuracy assessment. This implementation was used to screen the entire EPA DSSTox database of ∼875,000 chemicals, and their predicted AR activities have been made available on the EPA CompTox Chemicals dashboard and National Toxicology Program's Integrated Chemical Environment. https://doi.org/10.1289/EHP5580.

New Insights into the Binding Mechanism of Co-regulator BUD31 to AR AF2 Site: Structural Determination and Analysis of the Mutation Effect.

INTRODUCTION: Androgen Receptor (AR) plays a pivotal role in the development of male sex and contributes to prostate cancer growth. Different from other nuclear receptors that bind to the co-regulator LxxLL motif in coregulator peptide interaction, the AR Ligand Binding Domain (LBD) prefers to bind to the FxxLF motif. BUD31, a novel co-regulator with FxxLF motif, has been demonstrated to suppress wild-type and mutated AR-mediated prostate cancer growth. METHODS: To find out the interaction mechanisms of BUD31 with WT/T877A/W741L AR complex, molecular dynamics simulations were employed to study the complex BUD31 and WT/mutant ARs. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) results demonstrated that T877A and W741L point mutations can reduce the binding affinity between BUD31 and AR. The RMSF and dynamic cross-correlation analysis indicated that amino acid point mutations can affect the motions of loop residues in the AR structure. RESULTS: These results indicated that AR co-regulator binding site AF2 can serve as a target for drug discovery to solve the resistance problem.

Structure-activity relationship analysis of 3-phenylpyrazole derivatives as androgen receptor antagonists.

Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, reminds the second leading cause of cancer-related incidence in men worldwidely. Androgen receptor antagonists are the main therapeutic strategy of PCa, which can block the binding of androgen to androgen receptors. However, the long-term treatment of marketed anti-androgens in patients can inevitably cause drug resistance problem. The research of searching for new drugs with novel skeleton is always on the way. Recently, a series of 3-phenylpyrazole derivatives were reported to antagonize the function of AR, but their efficiencies are not good enough and need to be improved. In this work, comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to study the structure activity relationships of these derivatives. Two different methods were used to obtain the optimal molecular conformation alignments, one is based on atomic alignment and the other is based on molecular docking. The final result shows that both these two strategies can obtain satisfactory results and the atomic alignment performs a little better than docking. The models illustrate the key structural features highly related with the androgenic bioactivity and provide valuable suggestions for the design of new androgen receptor antagonists in future.Communicated by Ramaswamy H. Sarma.