A combination of molecular docking,receptor-guided QSAR,and molecular dynamics simulation studies of S-trityl-l-cysteine analogues as kinesin Eg5 inhibitors

Structural Chemistry - Kinesin Eg5 plays an essential role in the early stages of mitosis, and it is an interesting drug target for the design of potent inhibitors. In this work, combined molecular...     

Integrated 3D-QSAR,molecular docking,and molecular dynamics simulation studies on 1,2,3-triazole based derivatives for designing new acetylcholinesterase inhibitors

Alzheimer’s disease (AD) is a multifactorial and polygenic disease. It is the most prevalent reason for dementia in the aging population. A dataset of twenty-six 1,2,3-triazole-based derivatives previously synthetized and evaluated for acetylcholinesterase inhibitory activity were subjected to the three-dimensional quantitative structure-activity relationship (3D-QSAR) study. Good predictability was achieved for comparative molecular field analysis (CoMFA) (Q² = 0.604, R² = 0.863, r_ext² = 0.701) and comparative molecular similarity indices analysis (CoMSIA) (Q² = 0.606, R² = 0.854, r_ext² = 0.647). The molecular features characteristics provided by the 3D-QSAR contour plots were quite useful for designing and improving the activity of acetylcholinesterase of this class. Based on these findings, a new series of 1,2,3-triazole based derivatives were designed, among which compound A1 with the highest predictive activity was subjected to detailed molecular docking and compared to the most active compound. The selected compounds were further subjected to 20 ns molecular dynamics (MD) simulations to study the comparative conformation dynamics of the protein after ligand binding, revealing promising results for the designed molecule. Therefore, this study could provide worthy guidance for further experimental analysis of highly effective acetylcholinesterase inhibitors.     

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.     

3D-QSAR,docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors

Janus kinase 3 (JAK3) is a promising drug target for the treatment of inflammatory diseases, autoimmune disorders, organ transplant rejection and various cancers. In the present study, 3D-QSAR, docking, MD simulation and MM/PBSA studies were performed on a series of pyrimidine-based JAK3 inhibitors. A reliable COMSIA (q² = 0.717 and r² = 0.986) model was developed and validated using external validation test set, bootstrapping, progressive scrambling and r_m² metrics analyses. Structural requirements identified through contour maps of the model were strategically utilized to computationally design 170 novel JAK3 inhibitors with improved potency. Docking studies were performed on the selected data set and newly designed compounds to show their binding mode and to identify important interacting residues inside the active site of JAK3. In addition, docking results of the selected designed compounds inside the active sites of JAK1, JAK2 and TYK2 indicated their JAK3 selectivity. MD simulation (100 ns) on the docked complex of compound 28 (one of highly active compounds of the data set) assisted in the further exploration of the binding interactions. Some crucial residues like Lys830 (glycine-rich loop), Val836, Ala853, Leu905 (hinge region), Cys909, Asn954, Leu956 and Ala966 were identified. Hydrogen bond interactions with hinge residue Leu905 were critical for the binding of JAK3 inhibitors. Additionally, MM/PBSA calculation provided the binding free energy of the compound 28. Newly designed molecules showed promising results in the preliminary in silico ADMET evaluations. Outcomes of the study can further be exploited to develop potent JAK3 inhibitors.     

Pharmacophore modeling,atom based 3D-QSAR,molecular docking and molecular dynamics studies on Escherichia coli ParE inhibitors

ATP dependent ParE enzyme is as an attractive target for the development of antibacterial agents. Atom based 3D-QSAR model AADHR.187 was developed based on the thirty eight Escherichia coli ParE inhibitors. The generated model showed statistically significant coefficient of determinations for the training (R² = 0.985) and test (R² = 0.86) sets. The cross-validated correlation coefficient (q2) was 0.976. The utility of the generated model was validated by the enrichment study. The model was also validated with structurally diverse external test set of ten compounds. Contour plot analysis of the generated model unveiled the chemical features necessary for the E. coli ParE enzyme inhibition. Extra-precision docking result revealed that hydrogen bonding and ionic interactions play a major role in ParE protein-ligand binding. Binding free energy was computed for the data set inhibitors to validate the binding affinity. A 30-ns molecular dynamics simulation showed high stability and effective binding of inhibitor 34 within the active site of ParE enzyme. Using the best fitted model AADHR.187, pharmacophore-based high-throughput virtual screening was performed to identify virtual hits. Based on the above studies three new molecules are proposed as E. coli ParE inhibitors with high binding affinity and favourable ADME properties.     

3D-QSAR,molecular docking and ADMET studies of thioquinazolinone derivatives against breast cancer

Breast cancer is a deadly disease and the second largest cause of mortality on a worldwide platform. Despite the availability of several cancer treatments, life expectancies stay relatively poor. Consequently, the medicinal chemistry community prioritizes the quick discovery of novel anticancer drugs. In recent years, computational approaches have been widely used to accelerate the drug development process. In light of this, in the current work, we performed three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking analyses on thioquinazolinone derivatives with aromatase enzyme (PDB: 3S7S). External validation was used to validate the prediction capabilities of the generated model. The best CoMSIA (comparative molecular similarity indices analysis) model exhibited the significant values of $Q^2$, $R^{2}and$ $R_{pred}^2$. These findings suggested that the electrostatic, hydrophobic and hydrogen bond donor and acceptor fields have a significant effect on inhibition of breast cancer. Thus, a number of innovative potent aromatase inhibitors were designed and their biological activities were predicted based on the best model. Furthermore, molecular docking studies were carried out for the designed compounds against breast cancer. Additionally, ADMET proprieties were used to evaluate drug-likeness of these novel drug candidates. The most active compounds found by these computational studies could be helpful for synthesis and testing as prospective future anti-cancer treatments.     

3D QSAR and molecular docking studies of benzimidazole derivatives as hepatitis C virus NS5B polymerase inhibitors

The urgent need for novel HCV antiviral agents has provided an impetus for understanding the structural requisites of NS5B polymerase inhibitors at the molecular level. Toward this objective, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 67 HCV NS5B polymerase inhibitors were performed using two methods. First, ligand-based 3D QSAR studies were performed based on the lowest energy conformations employing the atom fit alignment method. Second, receptor-based 3D QSAR models were derived from the predicted binding conformations obtained by docking all NS5B inhibitors at the allosteric binding site of NS5B (PDB ID: 2dxs). Results generated from the ligand-based model were found superior (r2cv values of 0.630 for CoMFA and 0.668 for CoMSIA) to those obtained by the receptor-based model (r2cv values of 0.536 and 0.561 for CoMFA and CoMSIA, respectively). The predictive ability of the models was validated using a structurally diversified test set of 22 compounds that had not been included in a preliminary training set of 45 compounds. The predictive r2 values for the ligand-based CoMFA and CoMSIA models were 0.734 and 0.800, respectively, while the corresponding predictive r2 values for the receptor-based CoMFA and CoMSIA models were 0.538 and 0.639, respectively. The greater potency of the tryptophan derivatives over that of the tyrosine derivatives was interpreted based on CoMFA steric and electrostatic contour maps. The CoMSIA results revealed that for a NS5B inhibitor to have appreciable inhibitory activity it requires hydrogen bond donor and acceptor groups at the 5-position of the indole ring and an R substituent at the chiral carbon, respectively. Interpretation of the CoMFA and CoMSIA contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. Taken together, the present 3D QSAR models were found to accurately predict the HCV NS5B polymerase inhibitory activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the benzimidazole derivatives in the data set.     

Combined 2D and 3D-QSAR,molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure–activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good ‘leave-one-out’ cross validated correlation coefficient (q²) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r²) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r²_pred) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called ‘glutamine-switch’, and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure–activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.     

3D-QSAR and docking studies on 2-arylbenzoxazole and linker-Y transthyretin amyloidogenesis inhibitors

Transthyretin (TTR), a plasma protein with a tetramer structure, could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer. These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR. A number of small molecules like 2-arylbenzoxazoles (ABZ) analogues are proposed as promising therapeutic strategy to treat amyloidosis. In this work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on series of 2-arylbenzoxazoles (ABZ) and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level. Significant correlation coefficients for ABZ series (CoMFA, r ² = 0.877, q ² = 0.431; CoMSIA, r ² = 0.836, q ² = 0.447) and those for linker-Y series (CoMFA, r ² = 0.828, q ² = 0.522; CoMSIA, r ² = 0.800, q ² = 0.493) were obtained, and the generated models were validated using test sets. In addition, docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR. These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.     

噁唑-苯甲酰胺类FtsZ受体抑制剂的3D-QSAR研究

FtsZ蛋白和细菌的繁殖过程有关,是药物设计理想的靶点。本文采用Sybyl分子模拟软件,利用比较分子场方法(CoMFA)及比较分子相似性指数的方法(CoMSIA)对已报道的33个噁唑-苯甲酰胺类FtsZ受体抑制剂进行了分析,建立了三维定量构效关系(3D-Qsar)模型。CoMFA模型的交互验证系数q2为0.619,线性回归系数r2为0.988;CoMSIA模型的q2为0.633,r2为0.936。模型具有较好的预测能力,为今后噁唑-苯甲酰胺类化合物的设计和改造提供了理论依据。     

Molecular modelling studies on cinnoline-based BTK inhibitors using docking and structure-based 3D-QSAR

ABSTRACT

BTK inhibitors have been proved as an effective target for B-cell malignancies. Ibrutinib is the most advanced irreversible BTK inhibitor for treating mantle cell lymphoma/chronic lymphocytic leukaemia but with existing drug resistance and adverse effects. To design novel effective and safety reversible BTK inhibitors, 115 newly cinnoline analogues were selected to perform molecular docking and 3D-QSAR study because of the main scaffold similarity to Ibrutinib. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions are preferred at R₁ and R₃ positions, and introducing hydrophilic and negative electrostatic substitutions at R₁ positions is important for improving BTK inhibitory activities. These results will be useful to provide clues for rationally designing novel and high potency BTK inhibitors.     

3D-QSAR study,docking molecular and simulation dynamic on series of benzimidazole derivatives as anti-cancer agents

Benzimidazole is an important heterocyclic organic compound which has a structural analogy to nucleotides found in human body and hence is an important pharmacophore in medicinal chemistry. The anti-cancer activities for a diverse set of benzimidazole as anti-cancer agents against breast cancer cell line (MCF7) assay have been subjected to 3D-QSAR (3-Dimensional Quantitative Structural-Activity Relationship) studies. Both CoMFA and CoMSIA models exhibit significant results in terms of statistical parameters as determination coefficients R² > 0.9 and Leave One Out cross-validation determination coefficients Q²> 6. The predictive quality of both 3D QSAR models have been assessed by external validation and Y-randomization test. Five new compounds have been designed and predicted by in silico ADMET method. In the second part, we have used the docking molecular and simulation dynamics (MD) to investigate the bonding interactions and stability of the designed compounds into the Pin1. Then, we have compared them to Trastuzumab and Tamoxifen as a standard inhibitors drug of breast cancer. The designed compounds form stable hydrogen and hydrophobic bonding interactions with the residues Lys63, Gln131, Ser154, Arg 68 and Arg69 of Pin1 receptor during 100 ns as a time of the simulation. The obtained results showed that the new benzimidazole are useful as a template for future design of more potent inhibitors against breast cancer cell lines (MCF7).     

Atom-based 3D-QSAR,molecular docking,DFT, and simulation studies of acylhydrazone,hydrazine, and diazene derivatives as IN-LEDGF/p75 inhibitors

Structural Chemistry - Since HIV-1 integrase makes use of host genome machinery to accomplish the replication process, where LEDGF/p75 (a cellular cofactor) executes in the lentiviral integration...     

Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5

Monastrol, a cell-permeable inhibitor of the kinesin Eg5, has been used to probe the dynamic organization of the mitotic spindle. The mechanism by which monastrol inhibits Eg5 function is unknown. We found that monastrol inhibits both the basal and the microtubule-stimulated ATPase activity of the Eg5 motor domain. Unlike many ATPase inhibitors, monastrol does not compete with ATP binding to Eg5. Monastrol appears to inhibit microtubule-stimulated ADP release from Eg5 but does not compete with microtubule binding, suggesting that monastrol binds a novel allosteric site in the motor domain. Finally, we established that (S)-monastrol, as compared to the (R)-enantiomer, is a more potent inhibitor of Eg5 activity in vitro and in vivo. Future structural studies should help in designing more potent Eg5 inhibitors for possible use as anticancer drugs and cell biological reagents.     

基于雌激素β受体结构雌激素类化合物的三维定量结构-活性关系与分子对接研究

雌激素类化合物由于其对人和野生动物健康的负面影响而受到广泛关注.雌激素受体存在α和β两种亚型,由于雌激素β受体（ERβ）与α受体（ERα）两者结合腔中的氨基酸序列存在明显差异,因此配体化合物在与雌激素β受体和α受体的结合活性和模式上也可能存在较大差别.本文以50个与雌激素β受体结合的化合物为研究对象,应用比较分子相似性指数分析（COMSIA）的三维定量结构-活性关系（3D-QSAR）分析方法研究化合物结构与活性之间的关系,比较了原子契合和基于受体结构两种分子叠合方式对模型质量的影响,建立了相关性显著、预测能力强的定量活性预测模型（R^2=0.961,qLOO^2=0.671,R^2Pred=0.722）,并结合分子对接方法揭示了影响化合物活性的分子结构特征和分子机理.     

Use of hydrogen/deuterium exchange mass spectrometry and mutagenesis as a tool to identify the binding region of inhibitors targeting the human mitotic kinesin Eg5

An experimental procedure associating both hydrogen/deuterium exchange mass spectrometry (H/D-MS) and mutagenesis was developed to identify the protein-binding region of small inhibitors targeting the motor domain of the human mitotic kinesin Eg5. All the tested inhibitors decrease the deuterium incorporation rate of the same peptides corresponding to the following secondary structure elements: loop L5/helix alpha2 (region Tyr125-Glu145) and strand beta5/helix alpha3 (region Ile202-Leu227). Replacement of these two regions by the equivalent ones from N. crassa conventional kinesin heavy chain completely abolishes the modification of the deuterium incorporation rate by the inhibitors as well as their effects on the basal ATPase activity. The six tested inhibitors thus share a common binding site on Eg5. The strategy reported here allows the regions of a protein involved in ligand binding to be rapidly pinpointed and can be applied to other proteins and used as a general in vitro screening procedure to identify compounds targeting specific binding regions.