Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure-activity correlation of indolinone-based PDK1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling study. The study has resulted in two types of satisfactory 3D-QSAR models, including the CoMFA model (r(2)=0.907; q(2)=0.737) and CoMSIA model (r(2)=0.991; q(2)=0.824), for predicting the biological activity of new compounds. The detailed microscopic structures of PDK1 binding with inhibitors have been studied by molecular docking. We have also developed docking-based 3D-QSAR models (CoMFA with q(2)=0.729; CoMSIA with q(2)=0.79). The contour maps obtained from the 3D-QSAR models in combination with the docked binding structures help to better interpret the structure-activity relationship. All of the structural insights obtained from both the 3D-QSAR contour maps and molecular docking are consistent with the available experimental activity data. This is the first report on 3D-QSAR modeling of PDK1 inhibitors. The satisfactory results strongly suggest that the developed 3D-QSAR models and the obtained PDK1-inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.     

二芳基取代-1,2,4-三唑类化合物的合成及其抗炎活性研究

以选择性环氧化酶-2(COX-2)抑制剂Celecoxib为先导,根据其构效关系和分子模拟研究结果,应用生物电子等排原理等药物设计方法,设计合成了19个结构全新的二芳基取代-1,2,4-三唑类衍生物,其结构经IR,¹HNMR,MS和元素分析确证.初步的药理试验结果表明,部分目标化合物具有一定的抗炎活性.     

Development of energetic pharmacophore for the designing of 1,2,3,4-tetrahydropyrimidine derivatives as selective cyclooxygenase-2 inhibitors

We present here the Energetic pharmacophore model representing complementary features of the 1,2,3,4-tetrahydropyrimidine for selective cyclooxygenase-2 (COX-2) inhibition. For the development of pharmacophore hypothesis, a total of 43 previously reported compounds were docked on active site of COX-2 enzyme. The generated pharmacophore features were ranked using energetic terms of Glide XP docking for 1,2,3,4-tetrahydropyrimidine scaffold to optimize its structure requirement for COX-2 inhibition. The thirty new 4,5,6-triphenyl-1,2,3,4-tetrahydropyrimidine derivatives were synthesized and assessed for selective COX-2 inhibitory activity. Two compounds 4B1 and 4B11 were found to be potent and selective COX-2 inhibitors. The molecular docking studies revealed that the newly synthesized compounds can be docked into COX-2 binding site and also provide the molecular basis for their activity.     

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.     

New benzothiazole/benzoxazole-pyrazole hybrids with potential as COX inhibitors: design,synthesis and anticancer activity evaluation

Ten new hybrids were designed and synthesized, their chemical structures were confirmed through spectral and elemental analysis. The new hybrids were screened against lung, breast and liver cancer cell lines (A549, MCF7 and Hep3B), in addition to normal fibroblast cells. Compound 13a was the most active and selective one on the lung cancer cell line (A549), its IC₅₀ and S.I. values were 2.4 µM and 83.2, respectively. Compound 14b was active on MCF7 with the best selectivity towards this cell line. The new derivatives were screened for their inhibitory activity against COX enzymes, the obtained results revealed that compound 13a and 14b were more active inhibitors for COX-2 than celecoxib. This finding encourages us to consider COX-2 inhibitory activity as a proposed mechanism for their anticancer activity.     

Microscopic binding of butyrylcholinesterase with quinazolinimine derivatives and the structure–activity correlation

Butyrylcholinesterase (BChE) is not only an important protein for development of anti-cocaine medication but also an established drug target to develop new treatment for Alzheimer’s disease (AD). The molecular basis of interaction of a new series of quinazolinimine derivatives as BChE inhibitors has been studied by molecular docking and molecular dynamics (MD) simulations. The molecular docking and MD simulations revealed that all of these inhibitors bind with BChE in similar binding mode. Based on the similar binding mode, we have carried out three-dimensional quantitative structure–activity relationship (3D-QSAR) studies on these inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), to understand the structure–activity correlation of this series of inhibitors and to develop predictive models that could be used in the design of new inhibitors of BChE. The study has resulted in satisfactory 3D-QSAR models. We have also developed ligand-based 3D-QSAR models. The contour maps obtained from the 3D-QSAR models in combination with the simulated binding structures help to better interpret the structure–activity relationship and is consistent with available experimental activity data. The satisfactory 3D-QSAR models strongly suggest that the determined BChE-inhibitor binding modes are reasonable. The identified binding modes and developed 3D-QSAR models for these BChE inhibitors are expected to be valuable for rational design of new BChE inhibitors that may be valuable in the treatment of Alzheimer’s disease.     

Discovery of 5-Methylthiazole-Thiazolidinone Conjugates as Potential Anti-Inflammatory Agents: Molecular Target Identification and In Silico Studies

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure–activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors.     

用分子模拟方法研究HIV-1整合酶与咖啡酰基类抑制剂的相互作用

用分子对接和分子动力学(MD)模拟方法研究了一类咖啡酰基和没食子酰基类HIV-1整合酶抑制剂与整合酶之间的相互作用模式, 结果表明该类抑制剂分子上的两个侧链基团(咖啡酰基或没食子酰基)与整合酶的DDE基序之间的相互作用对抑制整合酶活性起到关键作用. 当侧链基团为没食子酰基时, 可以提高该类抑制剂与整合酶的结合能力. 采用线性相互作用能方法(LIE)计算了该类抑制剂与整合酶之间的结合自由能, 预测值与实验值相吻合, 均方根偏差RMSD为1.39 kJ•mol^-1, 以上结果可为基于结构的HIV-1整合酶抑制剂设计提供有用的信息.     

Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors

In an attempt to rationalize the search for new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines the prediction of physicochemical and pharmacokinetic properties, molecular docking, molecular dynamic simulation, and free energy calculation. Starting from a small library of compounds synthesized previously, it was found that 70% of the compounds analyzed satisfy with the associated values to physicochemical principles as key evaluation parameters for the drug-likeness; all the compounds presented good gastrointestinal absorption and cerebral permeability and they showed an interaction with the Arg 106 residue of the COX-2 isoenzyme. Finally, it was obtained that compound 3ab has a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug celecoxib, suggesting that this compound could become a powerful candidate in the inhibition of the COX-2 enzyme. In addition, we realized the crystallographic analysis of compounds 3j, 3r, and 3t defining the crystal parameters and the Packing interactions.     

Cyclooxygenase-2 inhibitors modulate skin aging in a catalytic activity-independent manner

It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1.     

Molecular docking and competitive binding study discovered different binding modes of microsomal prostaglandin E synthase-1 inhibitors

Microsomal prostaglandin E synthase-1 (mPGES-1) is a newly recognized therapeutic target for the treatment of inflammation, pain, cancer, atherosclerosis, and stroke. Many mPGES-1 inhibitors have been discovered. However, as the structure of the binding site is not well-characterized, none of these inhibitors was designed based on the mPGES-1 structure, and their inhibition mechanism remains to be fully disclosed. Recently, we built a new structural model of mPGES-1 which was well supported by experimental data. Based on this model, molecular docking and competition experiments were used to investigate the binding modes of four representive mPGES-1 inhibitors. As the inhibitor binding sites predicted by docking overlapped with both the substrate and the cofactor binding sites, mPGES-1 inhibitors might act as dual-site inhibitors. This inhibitory mechanism was further verified by inhibitor-cofactor and inhibitor-substrate competition experiments. To investigate the potency-binding site relationships of mPGES-1 inhibitors, we also carried out molecular docking studies for another series of compounds. The docking results correlated well with the different inhibitory effects observed experimentally. Our data revealed that mPGES-1 inhibitors could bind to the substrate and the cofactor binding sites simultaneously, and this dual-site binding mode improved their potency. Future rational design and optimization of mPGES-1 inhibitors can be carried out based on this binding mechanism.     

VEGFR2活性腔性质以及与抑制剂的结合模式研究

VEGFR2介导肿瘤诱导的血管生成作用, 是抑制肿瘤生长和转移的新靶点. 为深入探讨VEGFR2活性腔性质以及与抑制剂的结合模式, 采用多拷贝同时搜寻法(MCSS)研究VEGFR2活性腔的性质, 然后用分子对接方法对5个已上临床的VEGFR抑制剂与VEGFR2活性腔进行对接计算, 讨论它们的结合模式, 确定与配体结合相关的关键残基. 研究发现: 疏水腔I, II是配体结合的关键区域, 残基Glu915, Cys917是关键的氢键作用位点, Lys866, Glu883和Asp1044形成的极性区域对提高配体亲合力很重要, 疏水腔III和极性腔IV是额外增强配体结合力的区域, IV区的Arg1030可提供额外的氢键作用位点. 本研究可为全新VEGFR2抑制剂的合理药物设计提供理论依据, 为寻找新的抗肿瘤药物奠定基础.     

Synthesis,anticancer evaluation,and docking studies of some novel azo chromene derivatives

We have described a simple, convenient, and high-yielding one-pot synthesis of novel azo chromene derivatives via a three-component reaction of various azo aldehydes with dimedone and malononitrile using 10 mol% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst and ethanol as solvent at reflux condition. All the synthesized compounds have been characterized using Fourier-transform infrared spectroscopy (FT-IR), ¹H NMR, ¹³C NMR, and HR-MS spectra and molecular docking was performed to explore new inhibitors of human placental aromatase cytochrome P450 and cyclooxygenase-2 enzymes. Of all the compounds docked, compound (E)-2-amino-4-(4,4-dimethyl-2,6-dioxocyclohexyl)-6-((3-methoxyphenyl)diazenyl-4H-chromene-3-carbonitrile ( 4o ) showed good binding affinity with the active site of human placental aromatase cytochrome P450 enzyme (PDB: 3EQM) with inhibition constant (Ki) 1.66 nM and compound 4o also showed good binding affinity with the active site of cyclooxygenase-2 enzyme (PDB: 6COX) with inhibition constant (Ki) 367.17 pM. In vitro anti-cancer activity studies against MCF-7 cells were also performed for compounds 4o , anastrozole and celecoxib. Compound 4o showed an effective cytotoxicity at 19.8 μg/ml compared to anastrozole and celecoxib (24.7 and 26.2 μg/ml).     

COX抑制剂——氟比洛芬衍生物的作用方式及选择性研究

用DOCK4.0程序搜索氟比洛芬衍生物与环氧合酶结合的构象。用Cscore综合评 分体系确定最佳构象，复合物经分子力学优化后，发现衍生物在COX-1中的取向和 位置与X射线衍射测犁晶体复合物中氟比洛芬作用方式相同；衍生物在COX-2中也有 与氟比洛芬类似的结合方式。衍生物对COX-2/COX-1 的选择掏性与衍生物作用于两 种酶的结合自由能之差有较好的相关性。相关系数     

Studies of Interaction Mechanism between Pyrido [3,4-d] Pyrimidine Inhibitors and Mps1

Monopolar spindle 1 (Mps1), a dual-specific kinase, is related to the proper execution of chromosome biorientation and mitotic checkpoint signaling. The overexpression of Mps1 promotes the occurrence of cancer or the survival of aneuploid cancer cells, in other words, the reduction of Mps1 will severely reduce the viability of human cancer cells. Therefore, Mps1 is a potential target for cancer treatment. Recently, a series of novel pyrido [3,4-d] pyrimidine derivatives targeting Mps1 with high biological activity were synthesized. The crystal structure of Mps1 in complex with pyrido [3,4-d] pyrimidine derivatives was also reported, but there were no specific mechanism studies for this series of small molecule inhibitors. In this study, complexes binding modes were probed by molecular docking and further validated by molecular dynamics simulations and the molecular mechanics/generalized Born surface area (MM/GBSA) method. The results indicated that the van der Waals interactions and the nonpolar solvation energies were responsible to the basis for favorable binding free energies, all inhibitors interacted with residues I531, V539, M602, C604, N606, I607, L654, I663, and P673 of Mps1. By analyzing the hydrogen bonds, we found the residues G605 and K529 in Mps1 formed stable hydrogen bonds with compounds, it was more conducive to activities of Mps1 inhibitors. According to the above analysis, we further designed five new compounds. We found that compounds IV and V were better potential Mps1 inhibitors through docking and ADMET prediction. The obtained new insights not only were helpful in understanding the binding mode of inhibitors in Mps1, but also provided important references for further rational design of Mps1 inhibitors.     

Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that cyclooxygenase-1 (COX-1) plays an important role in inflammation and carcinogenesis. In order to find more selective COX-1 inhibitors a series of novel curcumin derivatives was synthesized and evaluated for their ability to inhibit this enzyme using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. All curcumin analogues showed a higher rate of COX-1 inhibition. The most potent curcumin compounds were (1E,6E)-1,7-di-(2,3,4-trimethoxyphenyl)-1,6-heptadien-3,5-dione (4) (COX-1: IC(50) = 0.06 microM, COX-2: IC(50) > 100 microM, selectivity index>1666) and (1E,6E)-methyl 4-[7-(4-methoxycarbonyl)phenyl]-3,5-dioxo-1,6-heptadienyl]benzoate (6) (COX-1: IC(50) = 0.05 microM, COX-2: IC(50) > 100 microM, selectivity index > 2000). Curcumin analogues therefore represent a novel class of highly selective COX-1 inhibitors and promising candidates for in vivo studies.     

Synthesis and biological evaluation of novel sulfonanilide compounds as antiproliferative agents for breast cancer

Combinatorial chemistry approaches facilitate drug discovery processes and result in structural modifications of lead compounds that enhance pharmacological activity, improve pharmacokinetic properties, or reduce unwanted side effects. Epidemiological and animal model studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) can act as chemopreventive agents. The cyclooxygenase-2 (COX-2) inhibitor nimesulide shows anticancer effects in several cancer cell lines via COX-2-dependent and -independent mechanisms. The molecular structure of nimesulide was used as a starting scaffold to design novel sulfonanilide analogs and examine the structural features that contribute to this anticancer effect. A systematic combinatorial chemical approach was used to generate diversely substituted sulfonanilide derivatives that were tested for their effects on the proliferation of human breast cancer cells. Structure-function analysis indicated that the inhibition of cell growth by compounds derived from the novel sulfonanilides required a bulky terminal phenyl ring, a methanesulfonamide, and a hydrophobic carboxamide moiety.