Molecular modeling of tricyclic compounds with anilino substituents and their intercalation complexes with DNA sequences

Although 9-anilinoacridines are among the best studied antitumoral intercalators, there are few studies about the effect of isosteric substitution of a benzene moiety for a heterocycle ring in the acridine framework. According to these studies, this approach may lead to effective cytotoxic agents, but good cytotoxic activity depends on structural requirements in the aniline ring which differ from those in 9-anilinoacridines. The present paper deals with molecular modeling studies of some 9-anilino substituted tricyclic compounds and their intercalation complexes (in various DNA sequences) resulting from docking the compounds into various DNA sequences. As expected, the isosteric substitution in 9-anilinoacridines influences the LUMO energy values and orbital distribution, the dipole moment, electrostatic charges and the conformation of the anilino ring. Other important differences are observed during the docking studies, for example, changes in the spatial arrangement of the tricyclic nucleus and the anilino ring at the intercalation site. Semiempirical calculations of the intercalation complexes show that the isosteric replacement of a benzene ring in the acridine nucleus affects not only DNA affinity but also base pair selectivity. These findings explain, at least partially, the different structural requirements observed in several 9-anilino substituted tricyclic compounds for cytotoxic activity. Thus, the data presented here may guide the rational design of new agents with different DNA binding properties and/or a cytotoxic profile by isosteric substitution of known intercalators.     

Molecular modeling of tricyclic compounds with anilino substituents and their intercalation complexes with DNA sequences

Although 9-anilinoacridines are among the best studied antitumoral intercalators, there are few studies about the effect of isosteric substitution of a benzene moiety for a heterocycle ring in the acridine framework. According to these studies, this approach may lead to effective cytotoxic agents, but good cytotoxic activity depends on structural requirements in the aniline ring which differ from those in 9-anilinoacridines. The present paper deals with molecular modeling studies of some 9-anilino substituted tricyclic compounds and their intercalation complexes (in various DNA sequences) resulting from docking the compounds into various DNA sequences. As expected, the isosteric substitution in 9-anilinoacridines influences the LUMO energy values and orbital distribution, the dipole moment, electrostatic charges and the conformation of the anilino ring. Other important differences are observed during the docking studies, for example, changes in the spatial arrangement of the tricyclic nucleus and the anilino ring at the intercalation site. Semiempirical calculations of the intercalation complexes show that the isosteric replacement of a benzene ring in the acridine nucleus affects not only DNA affinity but also base pair selectivity. These findings explain, at least partially, the different structural requirements observed in several 9-anilino substituted tricyclic compounds for cytotoxic activity. Thus, the data presented here may guide the rational design of new agents with different DNA binding properties and/or a cytotoxic profile by isosteric substitution of known intercalators.     

Theoretical studies on binding modes of copper-based nucleases with DNA

In the present work, molecular simulations were performed for the purpose of predicting the binding modes of four types of copper nucleases (a total 33 compounds) with DNA. Our docking results accurately predicted the groove binding and electrostatic interaction for some copper nucleases with B-DNA. The intercalation modes were also reproduced by “gap DNA”. The obtained results demonstrated that the ligand size, length, functional groups and chelate ring size bound to the copper center could influence the binding affinities of copper nucleases. The binding affinities obtained from the docking calculations herein also replicated results found using MM-PBSA approach. The predicted DNA binding modes of copper nucleases with DNA will ultimately help us to better understand the interaction of copper compounds with DNA.     

Internal abstraction of dynemicin A: An MD approach

Dynemicin A has the ability to undergo the Bergman cyclization, forming a para-benzyne moiety with the ability to induce DNA strand scission. This property of dynemicin A makes it a promising anti-tumor agent. Past research has shown conclusively that dynemicin A binds to and abstracts a hydrogen atom (H5′) from the DNA backbone, but the molecular mechanism of the binding event is not fully understood. We have used AMBER Molecular Dynamics simulations to investigate the dynamics associated with the reaction mechanisms. Previously, two binding mechanisms have been proposed, of which the second is more supported: (1) dynemicin A intercalates between two base pairs and directly abstracts a hydrogen atom from DNA and (2) dynemicin A inserts into the minor groove and directly abstracts a hydrogen atom from DNA. We propose a third mechanism, where dynemicin A intercalates, then undergoes a proximate, intramolecular hydrogen atom abstraction (internal abstraction). While not studied here, the resulting radical would then subsequently abstract a hydrogen atom from DNA.     

Structure-based designing of sordarin derivative as potential fungicide with pan-fungal activity

Fungal infections have become a significant problem for immunosuppressed patients. Sordarin, a promising fungicidal agent, inhibits fungal protein synthesis by impairing elongation factor-2 (eEF2) function. Intriguingly, despite high sequence similarity among eEF2s from different species, sordarin has been shown to inhibit translation specifically in certain fungi while unable to do so in some other fungal species (e.g. Candida parapsilosis and Candida lusitaniae).The sordarin binding site on eEF2 as well as its mechanism of action is known. In a previous study, we have detailed the interactions between sordarin and eEF2 cavities from different fungal species at the molecular level and predicted the probable cause of sordarin sensitivity.Guided by our previous analysis, we aimed for computer-aided designing of sordarin derivatives as potential fungicidal agents that still remain ineffective against human eEF2. We have performed structural knowledge-based designing of several sordarin derivatives and evaluated predicted interactions of those derivatives with the sordarin-binding cavities of different eEF2s, against which sordarin shows no inhibitory action. Our analyses identify an amino-pyrrole derivative as a good template for further designing of promising broad-spectrum antifungal agents. The drug likeness and ADMET prediction on this derivative also supports its suitability as a drug candidate.     

Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing -Phe Psi Pro- core and displaying favourable ADME-related properties

Aspartic protease (PR) of HIV-1 virus represents a valid therapeutic target for the design of antiviral agents suitable for treatment of AIDS. We have designed peptidomimetic PR inhibitors containing a novel dihydroxyethylenediamine -Phe-Psi[CHOH-CHOH]-Pro- core using molecular modelling approach that predicts the inhibitory potencies (IC(50)(pre)) in terms of computed relative enzyme-inhibitor complexation Gibbs free energies (Delta Delta G(comp)). The modelling approach considers not only the enzyme-inhibitor interactions, but includes also the solvent and entropic effects affecting the enzyme inhibition. The objectives of this study were to optimize the number and type of flanking residues that occupy the S(3), S(2) and S(2'), S(3') positions in the PR binding pocket and to select potent lead candidates, which display also favourable ADME-related properties. The structure-based design was combined with a synthetic strategy used to prepare a training set of 10 analogues sharing the -Phe Psi Pro- core. This strategy couples stereochemical control with full flexibility in the choice of the flanking residues and in vitro activity assays. A QSAR model correlating calculated Delta Delta G(comp) with the measured IC(50)(exp) values for the training set was prepared and confirmed that our computational approach can serve for reliable prediction of PR inhibitory potencies of peptidomimetics. The appropriate choice of the flanking residues allowed us to design virtual lead compounds, such as FP14, FP23 and FP76, with reduced molecular weight, predicted inhibitory potencies in the picomolar range, promising ADME profiles and a potential to escape drug resistance due to favourable interactions with the PR backbone.     

3D-QSAR and molecular docking studies of selective agonists for the thyroid hormone receptor beta

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) on a series of agonists of thyroid hormone receptor beta (TRbeta), which may lead to safe therapies for non-thyroid disorders while avoiding the cardiac side effects. The reasonable q(2) (cross-validated) values 0.600 and 0.616 and non-cross-validated r(2) values of 0.974 and 0.974 were obtained for CoMFA and CoMSIA models for the training set compounds, respectively. The predictive ability of two models was validated using a test set of 12 molecules which gave predictive correlation coefficients (r(pred)(2)) of 0.688 and 0.674, respectively. The Lamarckian Genetic Algorithm (LGA) of AutoDock 4.0 was employed to explore the binding mode of the compound at the active site of TRbeta. The results not only lead to a better understanding of interactions between these agonists and the thyroid hormone receptor beta but also can provide us some useful information about the influence of structures on the activity which will be very useful for designing some new agonist with desired activity.     

Towards the identification of the binding site of benzimidazoles to β-tubulin of Trichinella spiralis: Insights from computational and experimental data

Benzimidazole-2-carbamate derivatives (BzC) are among the most important broad-spectrum anthelmintic drugs for the treatment of nematode infections. BzC selectively bind to the β-tubulin monomer and inhibit microtubule polymerization. However, the crystallographic structure of the nematode tubulin and the mechanism of action are still unknown. Moreover, the relation between the mechanism of action and the binding site of BzC has not yet been explained accurately. By using the amino acid sequence of Trichinella spiralis β-tubulin as a basis and by applying homology modeling techniques, we were able to build a 3D structure of this protein. In order to identify a binding site for BzC, molecular docking and molecular dynamics calculations were carried out with this model. The results were in good agreement with the most common amino acid mutations associated with drug resistance (F167Y, E198A and F200Y) and with the experimental results of competitive inhibition of colchicine binding to tubulin. Besides, Glu198, Thr165, Cys239 and Gln134 were identified as important amino acids in the binding process since they directly interact with BzC in the formation of hydrogen bonds. The results presented in this paper are a step further towards the understanding, at the molecular level, of the mode of action of anthelmintic drugs. These results constitute valuable information for the design or improvement of more potent and selective molecules.     

基于电磁超声导波的管道损伤定量评估

作为能源运输工具,管道在工作时会受到内部运输介质的冲刷和外部环境的腐蚀,导致强度下降并出现损伤。考虑不规则缺陷量化研究的局限性,并依据管道常见腐蚀缺陷类型,将腐蚀缺陷大致分为槽形、月牙形和圆形3种具有不同几何边界的类型。利用COMSOL软件建立电磁-力多物理场耦合的电磁超声L(0,2)模态导波管道缺陷检测3D模型,得到在不同类型缺陷作用下的超声波传播过程和接收信号特点。同时根据仿真结果,利用L(0,2)导波及其模态转换F(1,3)信号,拟合反射系数与缺陷几何参数间的定量关系,并通过实验加以验证。结果表明,缺陷形状为槽形、圆形、月牙形时,缺陷反射系数与截面损失率分别呈二次函数、对数、指数关系,各量化模型平均绝对百分比误差分别为2.67%、1.79%和7.91%。     

Caffeine as base analogue of adenine or guanine: A theoretical study

The results of quantum mechanical calculations, including binding energies and results of the population analysis show that the GC and AT base pair complexes are more stable than the CAF-X ones (where CAF is caffeine and X = adenine (A), thymine (T), cytosine (C) and guanine (G)). Structural similarity between the CAF molecule and purine bases (G and A) provides the possibility of incorporation of the CAF molecule into the DNA macromolecule. By comparing the CAF-A and CAF-T complexes with the AT base pair, and the CAF-G and CAF-C complexes with the GC base pair, it was found that the formation of the CAF-T complex is more probable than the other complexes. Thus, the CAF molecule acts as an analogue base of A and can be incorporated into the DNA macromolecule and paired with T and C in normal and rare state, respectively. Indeed, the results show that formation of the CAF-C complex is less probable than the CAF-T one and an AT to GC conversion is rarely occurred in the next DNA replication, so the CAF molecule may be considered as a weak mutagenic compound. To examine solvent effect, the binding energies have been calculated in solvent for the most important structures of the CAF-G, CAF-T, CAF-A and CAF-C complexes. The results in solvent are in agreement with those in the gas phase.     

Computational study of human phosphomannose isomerase: Insights from homology modeling and molecular dynamics simulation of enzyme bound substrate

Phosphomannose isomerase is a zinc metalloenzyme that catalyzes the reversible isomerization of mannose-6-phosphate and fructose-6-phosphate, and the three-dimensional (3D) structure of human phosphomannose isomerase has not been reported. In order to understand the catalytic mechanism, the 3D structure of the protein is built by using homology modeling based on the known crystal structure of mannose-6-phosphate isomerase from (PDB code 1PMI). The model structure is further refined by energy minimization and molecular dynamics methods. The mannose-6-phosphate-enzyme complex is developed by molecular docking and the key residues involved in the ligand binding are determined, which will facilitate the understanding of the action mode of the ligands and guide further genetic studies. Our results suggest a hydride transfer mechanism of alpha-hydrogen between the C1 and C2 positions but do not support the cis-enediol mechanism. The detailed mechanism involves, on one side, Zn2+ mediating the movement of a proton between O1 and O2, and, on the other side, the hydrophobic environment formed in part by Tyr278 promoting transfer of a hydride ion.     

Shape effects on the activity of synthetic major-groove binding ligands

In this work we present the results of a molecular simulation study of two different tetracationic bis iron(II) supramolecular cylinders interacting with DNA. One cylinder has been shown to bind in the major groove of DNA and to induce dramatic coiling of the DNA; the second is a derivative of the first, with additional methyl groups attached so as to give a larger cylinder-radius. The simulations show that both cylinders bind strongly to the major groove of the DNA, and induce complex structural changes in A–T rich regions. Whereas the parent cylinder tends to bind along the major groove, the derivatised cylinder tends to twist so that only one end remains within the major groove. Both G–C rich and A–T rich binding sites for the derivatised cylinder are discussed.     

Insight into the structural requirements of proton pump inhibitors based on CoMFA and CoMSIA studies

In the present study, a series of 179 quinoline and quinazoline heterocyclic analogues exhibiting inhibitory activity against Gastric (H+/K+)-ATPase were investigated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods. Both the models exhibited good correlation between the calculated 3D-QSAR fields and the observed biological activity for the respective training set compounds. The most optimal CoMFA and CoMSIA models yielded significant leave-one-out cross-validation coefficient, q(2) of 0.777, 0.744 and conventional cross-validation coefficient, r(2) of 0.927, 0.914 respectively. The predictive ability of generated models was tested on a set of 52 compounds having broad range of activity. CoMFA and CoMSIA yielded predicted activities for test set compounds with r(pred)(2) of 0.893 and 0.917 respectively. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity. The factors affecting activity were analyzed carefully according to standard coefficient contour maps of steric, electrostatic, hydrophobic, acceptor and donor fields derived from the CoMFA and CoMSIA. These contour plots identified several key features which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel peptic-ulcer inhibitors prior to their synthesis.     

Development of predictive in silico model for cyclosporine- and aureobasidin-based P-glycoprotein inhibitors employing receptor surface analysis

P-glycoprotein (Pgp) is implicated in multiple drug resistance (MDR) exhibited by several types of cancer against a multitude of anticancer chemotherapeutic agents. This problem prompted several research groups to search for effective P-gp inhibitors. Cyclosporine A (CsA), aureobasidin A (AbA) and related analogues were reported to possess potent inhibitory actions against Pgp. In this work we employed receptor surface analysis (RSA) to construct two satisfactory receptor surface models (RSMs) for cyclosporine- and aureobasidin-based Pgp inhibitors. These pseudoreceptors were combined to achieve satisfactory three-dimensional quantitative structure activity relationship (3D-QSAR) for 68 different cyclosporine and aureobasidin derivatives. Upon validation against an external set of 16 randomly selected Pgp inhibitors, the optimal 3D-QSAR was found to be self-consistent and predictive (r(LOO)(2)=0.673, r(PRESS)(2)=0.600). The resulting 3D-QSAR was employed to probe the structural factors that control the inhibitory activities of cyclosporine and aureobasidin analogues against Pgp.     

Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR,molecular docking,and dynamics simulation techniques

To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q²) and non-cross-validated correlation coefficient (r²) of the best CoMFA model are 0.715 and 0.992, respectively. The q² and r² values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10 ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.