Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors

The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket. Validation of the modelling process was achieved by comparing the predicted enzyme-bound conformation with the known conformation in the X-ray structure. The successful prediction of the binding conformation of the known inhibitors gave confidence that we could use our model to evaluate the binding conformation of the aminopyridazine compounds. The alignment of 42 aminopyridazine compounds derived by the docking procedure was taken as the basis for a 3D QSAR analysis applying the GRID/GOLPE method. A model of high quality was obtained using the GRID water probe, as confirmed by the cross-validation method (q² _LOO=0.937, q² _{L50% O}=0.910). The validated model, together with the information obtained from the calculated AChE-inhibitor complexes, were considered for the design of novel compounds. Seven designed inhibitors which were synthesized and tested were shown to be highly active. After performing our modelling study the X-ray structure of AChE complexed with donepezil, an inhibitor structurally related to the developed aminopyirdazines, has been made available. The good agreement found between the predicted binding conformation of the aminopyridazines and the one observed for donepezil in the crystal structure further supports our developed model.     

5-取代苯硫基-2,4-二氨基嘧啶类化合物的合成及其抑酶活性的定量构效关系研究

本文报道8个5-(取代苯硫基)-2,4-二氨基嘧啶类化合物的合成,测定了对E.coliMB1428 DHFR的抑制活性。对16个本类化合物进行Hansch分析表明,本类化合物对E·coli DHFR的抑制作用与3′,4′,5′-位取代基限制数值的立体参数呈线性关系,与取代基的疏水性参数呈双线性关系。     

结合QSAR、分子对接和动力学模拟剖析小分子与不同受体的结合亲和力

本文从三种不同的角度分析小分子与受体的结合情况,互相补充,为探讨不同类型结合模式提供有用的信息和研究手段。利用比较分子相似性指数法(CoMSIA)和分子全息定量构效关系法(HQSAR),建立一系列小分子与不同受体(AhR和TTR)亲和力活性数据的定量构效关系预测模型。结果表明模型均具有较高稳定性和预测能力(q~20.55,r~20.85)。同时,根据CoMSIA模型的等值线图和HQSAR模型的原子贡献图得出BDE154和BDE019与受体之间的结合作用方式,主要为疏水作用,带羟基基团化合物不利于与受体结合。此外,分子对接结果表明模型的结合力类型分别为疏水作用和π-π堆积作用。而分子动力学模拟的结果表明,随着小分子的加入,受体的二级结构发生转变。     

Molecular structural investigations of quinoxaline derivatives through 3D-QSAR,molecular docking,ADME prediction and pharmacophore modeling studies for the search of novel antimalarial agent

In the present article, a dataset of 63 quinoxaline derivatives were taken for antimalarial activity and pharmacophore were developed. Atom based method was used to develop a three dimensional quantitative structure activity relationship (3D-QSAR) model. On comparison of all statistical parameters, model AHRRR23 was found to be the most effective and predictive QSAR model as it satisfied all statistical parameters of a good model. The model AHRRR23 showed an adequate R² value for the training set 0.9446, good predictive power with Q² of 0.6409, good F- value, low SD 0.1218 value and outstanding Pearson-R values and low RMSE 0.2779 values of the model. The docking studies also gives very good results with good RMSD values. 3D QSAR, docking and ADME studies exhibits that the developed model could be employed as a potential lead for further study as antimalarial drug.     

Towards further understanding the structural insights of isoxazoles analogues against leishmaniasis using QSAR,molecular docking and molecular dynamics model

Leishmaniasis is one of the most well-known neglected infectious diseases, which is severe problem for public health. Heterocyclic derivatives are known to displays wide range of pharmacology activities including isoxazole ring that exhibit antileishmanial activity. Quantitative structure-activity relationship (QSAR) molecular docking and molecular dynamics are computational approaches to identify the relationships between structural properties and binding affinity of compounds. In the given paper series of 59, 4-aminomethyl 5-aryl-3-substituted isoxazoles were used to identify the structural insights and to find the binding affinity with protein. The designed model produced statistically significant results with of R² = 0.72, R²_adj = 0.65, and Q²_LMO = 0.72. Structure activity relationship (SAR) revealed that substitution of hydrophobic and steric groups may enhance the biological activity of compounds as antiprotozoal agents. Most potent compound formed hydrogen bonds with active amino acids Arg 87, Arg 104, Gly 112, His 117, Gly 118 and Asp 120. Molecular dynamics simulation (150 ns) on the docked complex of most active compound 3ba and 6 ab supported in the exploration of binding. Further MMPBSA investigations utilising MD trajectories verified compound 3bc higher binding affinity for nucleoside diphosphate kinases. The given strategies of computational studies could be an encouraging way for designing therapeutic targets against leishmaniasis.     

Homology model of the rainbow trout estrogen receptor (rtERα) and docking of endocrine disrupting chemicals (EDCs)‖

A model for rainbow trout (Oncorhynchus mykiss) estrogen receptor (rtERα) was built by homology with the human estrogen receptor (hERα). A high level of sequence conservation between the two receptors was found with 64% and 80% of identity and similarity, respectively. Selected endocrine disrupting chemicals were docked into the ligand binding domain (LBD) of rtERα and the corresponding free binding energies Δ(ΔG_bind) values were calculated. A Quantitative Structure-Activity Relationship (QSAR) model between the relative binding affinity data and the Δ(ΔG_bind) values was derived in order to predict which further organic pollutants are likely to bind to rtERα.

     

Effects of variable selection on CoMFA coefficient contour maps in a set of triazines inhibiting DHFR

Summary An example of a CoMFA study is described with the aim to discuss one of the major problems of this 3D QSAR method: lack of variable selection. It is shown that the use of nonrelevant energy parameters might produce CoMFA contour maps which poorly reflect the actual nature of the binding site and are in part statistical artefacts. The data set employed in our analysis comparises triazine inhibitors of dihydrofolate reductase (DHFR), isolated from chicken liver, which have already been the object of a QSAR study by other authors. Since three-dimensional structures of triazine-DHFR complexes are known, it was possible not only to reduce ambiguities in the superimposition of the ligands, but also to compare the resulting CoMFA contour maps with the enzyme active site.Supplementary material available: The Cartesian coordinates and the atomic charges of the PM3-optimized structures used in the CoMFA study are available as MOL2 files upon request.To whose memory this paper is dedicated.     

A pseudoreceptor docking study of 4,5-α-epoxymorphinans with a range of dielectric constants

Summary Thirteen 4,5-epoxymorphinan agonists with established analgesic action were docked into an Asp-Lys-His-Phe pseudoreceptor complex under a range of distance-dependent dielectric conditions. The number of compounds with potential energies of the docked complexes that agreed in rank order with corresponding analgesic potencies was determined for each condition. Two dielectric conditions, n-decane (1.991) and ethanol (24.3), enabled the greatest number of compounds to relate to their pseudoreceptors with each having 9 and 8 successes respectively. Both of these conditions demonstrated unique influences on the types of structures that were successfully docked. For example, the morphine stereoisomer -isomorphine, the geometric isomer B/C trans-morphine, and the 8-position-substituted -isomorphine were successes in the n-decane condition, whereas the ethanol condition produced the substituted codeine derivatives dihydroco-deinone and dihydroxycodeinone. These findings emphasize the importance of dielectric influence when developing force-field modeled quantitative structure-activity relationships for a closely related homologous series.     

Synthesis and Structure-Antitumor Activity of 4,6-Diamino-1,2-Dihydro-2, 2-Dimethyl-1-(Substituted-Naphthyl- 2)-1,3,5-Triazines

Introduction 4,6-Diamino-1,2-dihydro-2,2-dimethyl-1-substituted-1,3,5-triazines (Ⅰ) are dihydrofolate reductase(DHFR) inhibitors, hence they possess the inhibition to the growth of bacteria and cancer cells. Baker's antifolate (Ⅱ) has shown promise as an antitumor agertt in clinical trials. The study of the structure-activity relationships of I shows that the inhibition to vertebrate DHFR is significantly influenced by the hydrophobicity of 1-substituent, i.e., the stronger the hydrophobicity of the 1-substituent, the more potent the inhibition of the compound to vertebrate DHFR.     

Design, Synthesis and Molecular Docking of a Novel Small-molecule Inhibitor of Caspase-3

4,5-Dihydro-3-methylbenzo[1,2-b]furan-4,5-dione(4) was identified as a novel and potent inhibitor of caspase-3 through structural modification of an existing drug,sodium tanshinone ⅡA sulfonate(STS).Compound 4 showed high potency against caspase-3 in vitro(IC50=0.13 μmol/L).Molecular docking study further provided an insight into the interaction of compound 4 with activated caspase-3.Hence,this small-molecule caspase-3 inhibitor could be a promising therapeutic candidate against diseases caused by abnormally up-regulated apoptosis.