Computer-aided molecular design of some indolinone derivatives of PLK4 inhibitors as novel anti-proliferative agents

Among the most well-known members of the mitotic protein kinase family are polo-like kinases. Polo-like kinase 4 as a type of this family is used as a therapeutic target in the treatment of proliferative diseases. A three-dimensional quantitative structure activity relationship study with comparative molecular field analysis and comparative molecular similarity indices analysis was carried out on a data set of 47 molecules consisting of (E)-3-((1H-indazol-6-yl)methylene) indolin-2-ones derivatives of polo-like kinase 4 inhibitors to rational design of new drug. The validity of model was tested with a data set divided into training and test set. All constructed models show good statistical reliability in terms of predicting polo-like kinase inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. Moreover, molecular docking with CDOCKER algorithm was done to investigate interactions of between ligand and protein and to achieve bioactive ligand conformer. The energy difference between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (gap) implicitly stated the high reactivity of the most active molecule in the active site of protein. Furthermore, the molecular electrostatic potential energy at density functional theorylevel confirm the results from molecular docking. The identified key features obtained from the quantitative structure activity relationship modeling enabled us to design novel indolinone derivatives. In silico absorption, distribution, metabolism and excretion and toxicity risk assessment analyses were carried out on the new molecules to investigate compliance with the standard ranges.     

The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2

A set of 30 novel Delta8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed. These models were fitted with experimental binding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFA and CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFA and CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptors allowed us to deduce the possible optimal binding positions. This information can be used for the design of new CB analogues with enhanced activity and other tailored properties.     

Pharmacophore and QSAR studies to design novel histone deacetylase 2 inhibitors

One pharmacophore model and three quantitative structure-activity relationship models were developed on a series of benzimidazole and imidazole inhibitors of histone deacetylase 2. The goodness of hit score value of the best pharmacophore model was 0.756, which indicated that it is reliable to be used for virtual screening. The built pharmacophore model was used to search the NCI database. The hit compounds were subjected to molecular docking. The results showed that 25 compounds had high scores and strong interactions with histone deacetylase 2. In three-dimensional quantitative structure-activity relationship studies, good predictive models were obtained using comparative molecular field analysis, comparative molecular similarity indices analysis, and Topomer comparative molecular field analysis. Some putative active compounds were proposed based on compound no. 41. Twenty-six compounds had high scores and good interactions when they were docking into histone deacetylase 2.     

Development of quantitative structure-metabolism (QSMR) relationships for substituted anilines based on computational chemistry

Abstract

1. A novel stepwise classification approach for predicting the metabolic fate of substituted anilines, based on calculated physicochemical parameters of the parent anilines, was developed. Based on multivariate pattern recognition methods (PLS-DA or soft independent modelling of class analogy [SIMCA]), these models allowed prediction of N-acetylation and subsequent N-oxanilic acid formation. These classification methods provided an improved classification success when compared with existing quantitative structure-metabolism relationship models for substituted anilines.

2. Modelling the physicochemical properties of the N-acetylated compounds was considered as an addition to the stepwise model. Inclusion of parameters describing the N-acetyl moiety had little effect on the predictive ability of a stepwise parent to N-acetyl to N-oxanilic acid PLS-DA model, and had a negative impact on that of SIMCA models. This was attributed to the relatively small contribution to the total parameter variance caused by differences arising as a result of N-acetylation compared to the contribution made by the substituent effects.

3. Calculation of physicochemical properties incorporating the effect of solvation using ab initio methods improved the classification model in terms of both the visual separation in multivariate projections and prediction accuracy.     

Synthesis of 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as novel, potent, and selective alpha1-adrenoceptor ligands

Novel compounds characterized by a pyrrolo[3,2-d]pyrimidine-2,4-dione (PPm) system connected through an alkyl chain to a phenylpiperazine (PPz) residue were designed as structural analogues of the alpha(1)-adrenoceptor (alpha(1)-AR) ligand RN5 (1). In this new series of derivatives an arylpyrrolo moiety has replaced the indole nucleus of RN5. Several structural modifications were performed on the PPm and PPz moieties and the connecting alkyl chain. These compounds were synthesized and tested in radioligand binding experiments where many of them showed interesting binding profiles. Some compounds, including 31, 34, and 36, displayed substantial alpha(1)-AR selectivity with respect to serotoninergic 5-HT(1A) and dopaminergic D(1) and D(2) receptors. Two different molecular modeling approaches (pharmacophoric mapping and quantitative structure-affinity relationship analysis) have been applied to rationalize, at a quantitative level, the relationships between affinity toward alpha(1)-ARs and the structure of the studied compounds. Several QSAR models have been reported and described, accounting for the influence of various molecular portions on such affinity data.     

Three-dimensional structure-activity relationships of nonsteroidal ligands in complex with androgen receptor ligand-binding domain

We studied the three-dimensional quantitative structure-activity relationships (3D QSAR) of 70 structurally and functionally diverse androgen receptor (AR) binding compounds using the comparative molecular similarity indices analysis (CoMSIA) method. The compound set contained 67 nonsteroidal analogues of flutamide, nilutamide, and bicalutamide whose binding mode to AR was unknown. Docking was used to identify the preferred binding modes for the nonsteroidal compounds within the AR ligand-binding pocket (LBP) and to generate the ligand alignment for the 3D QSAR analysis. The alignment produced a statistically significant and predictive model, validated by random group cross-validation and external test sets (q(2)(LOO) = 0.656, SDEP = 0.576, r(2) = 0.911, SEE = 0.293; q(2)(10) = 0.612, q(2)(5) = 0.571; pred-r(2) = 0.800). Additional model validation comes from the CoMSIA maps that were interpreted with respect to the LBP structure. The model takes into account and links the AR LBP structure, docked ligand structures, and the experimental binding activities. The results provide valuable information on intermolecular interactions between nonsteroidal ligands and the AR LBP.     

4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor

A training set of 27 propofol (2,6-diisopropylphenol) analogues was used to construct four-dimensional (4D) quantitative structure-activity relationship (QSAR) models for three screens of biological activity: loss of righting reflex (LORR) in tadpoles, enhancement of agonist activity at the gamma-aminobutyric acid type A (GABA(A)) receptor, and direct (agonist-independent) activation of the receptor. The three resulting 4D-QSAR models are almost identical in form, and all suggest three key ligand-receptor interaction sites. The formation of an intermolecular hydrogen bond involving the proton of the ligand -OH group is the most important binding interaction. A hydrophobic pocket binding interaction involving the six-substituent is the second most significant binding site, and a similar hydrophobic pocket binding interaction near the two-substituent is the third postulated binding site from the 4D-QSAR models. A test set of eight compounds was used to evaluate the tadpole LORR 4D-QSAR model. Those compounds highly congeneric to the training set compounds were accurately predicted. However, compounds exploring substituent sites and/or electronic structures different from the training set were less well-predicted. Overall, the results show a striking similarity between the models of the sites responsible for anesthesia and those mediating effects of the training set of propofol analogues on the GABA(A) receptor; it follows that the GABA(A) receptor is therefore the likely site of propofol's anesthetic action.     

Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and Inhibition

To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4‐diazepane‐2,5‐diones inhibitors that explores the crucial molecular features contributing to binding specificity. Molecular docking studies of inhibitors within the active site of chymase were carried out to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. The density functional theory method was used to optimize molecular structures with the subsequent analysis of highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential maps, which revealed that negative potentials near 1,4‐diazepane‐2,5‐diones ring are essential for effective binding of inhibitors at active site of enzyme. The Bayesian model with receiver operating curve statistic of 0.82 also identified arylsulfonyl and aminocarbonyl as the molecular features favoring and not favoring inhibition of chymase, respectively. Moreover, genetic function approximation was applied to construct 3D quantitative structure–activity relationships models. Two models (genetic function approximation model 1 r² = 0.812 and genetic function approximation model 2 r² = 0.783) performed better in terms of correlation coefficients and cross‐validation analysis. In general, this study is used as example to illustrate how combinational use of 2D/3D quantitative structure–activity relationships modeling techniques, molecular docking, frontier molecular orbital density fields (highest occupied molecular orbital and lowest unoccupied molecular orbital), and molecular electrostatic potential analysis may be useful to gain an insight into the binding mechanism between enzyme and its inhibitors.     

Structural requirements at the melatonin receptor.

1. High affinity, specific binding sites for the pineal hormone, melatonin (5-methoxy N-acetyltryptamine) can be detected in chick brain membranes by use of the radiolabelled agonist, 2-[125I]-iodomelatonin (2-[125I]-aMT). 2. The affinity of a number of analogues of melatonin at the 2-[125I]-aMT binding site was determined and compared with an analysis of their electronic structure and significant quantitative relationships obtained. 3. The best correlations indicated that binding affinity was correlated with delta E, the difference between the frontier orbital energies, and QNH, the electron density in the highest occupied molecular orbital of the side-chain nitrogen atom. 4. These findings suggest that ligand binding may involve hydrogen bonding between the 5-methoxy and amide moieties of melatonin and complementary amino acid residues, and charge transfer interactions between the indole ring of melatonin and an aromatic amino acid in the receptor binding site. 5. A molecular model of a putative binding site is proposed based on the predicted amino acid sequence of the cloned Xenopus laevis melanophore melatonin receptor and the quantitative structure-affinity relationships observed in the present study.     

Relationship between chlorofluorocarbon chemical structure and their Salmonella mutagenicity

This paper is a quantitative analysis of the relationship between the chemical structure and the Salmonella mutagenicity of a number of chlorofluorocarbons (CFC). The molecules were characterized by both molecular orbital and physical chemical parameters. The results of the analysis indicated that the CFC mutagenicity is correlated with two parameters: the free energy of binding to biological receptors, and the energy of the highest occupied molecular orbital (HOMO). Since these are the same factors that would favor the cytochrome P-450-catalyzed metabolism, it would appear that the CFC mutagenicity is determined more by the rate of initial activation than by the rate of DNA attack.     

The Ligand-binding Site of Buspirone Analogues at the 5-HT1A Receptor

A three-dimensional model of the 5-HT_1A receptor in man was constructed by molecular-modelling techniques and used to study the molecular interactions of a series of buspirone analogues with the 5-HT_1A receptor by molecular-mechanical-energy minimization and molecular-dynamics simulations. The receptor has seven trans-membrane α helices (TMHs) organized according to the electron-density-projection map of visual rhodopsin, and includes all loops between TMHs and the N- and C-terminal parts. The best fit between the buspirone analogues and the receptor model was obtained with the quinolinyl part of the ligand molecules interacting with amino acids in TMH6, the imide group interacting with amino acids in TMH2, TMH3 and TMH7, and the carbonyl groups hydrogen-bonded with Ser86 and Ser393. The ligand-binding rank order deduced from the experimentally determined inhibition constant was reproduced by calculation of receptor-binding energies of the buspirone analogues. The models suggest that steric hindrance and repulsive forces between the receptor and the imide group of the buspirone analogues are the most important determinants of ligand-binding affinity for discriminating between these ligands.     

3D QSAR studies on cinnamaldehyde analogues as farnesyl protein transferase inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies on 59 cinnamaldehyde analogues as Farnesyl Protein Transferase (FPTase) inhibitors were investigated using comparative molecular field analysis (CoMFA) with the PLS region-focusing method. Forty-nine training set inhibitors were used for CoMFA with two different grid spacings, 2A and 1A. Ten compounds, which were not used in model generation, were used to validate the CoMFA models. After the PLS analysis, the best predictive CoMFA model showed that the cross-validated value (r2cv) and the non-cross validated conventional value (r2ncv) are 0.557 and 0.950, respectively. From the CoMFA contour maps, the steric and electrostatic properties of cinnamaldehyde analogues can be identified and verified.     

Novel mechanism for dehalogenation and glutathione conjugation of dihalogenated anilines in human liver microsomes: evidence for ipso glutathione addition

The objective of the present study was to investigate the influence of halogen position on the formation of reactive metabolites from dihalogenated anilines. Herein we report on a proposed mechanism for dehalogenation and glutathione (GSH) conjugation of a series of ortho-, meta-, and para-dihalogenated anilines observed in human liver microsomes. Of particular interest were conjugates formed in which one of the halogens on the aniline was replaced by GSH. We present evidence that a (4-iminocyclohexa-2,5-dienylidene)halogenium reactive intermediate (QX) was formed after oxidation, followed by ipso addition of GSH at the imine moiety. The ipso GSH thiol attacks at the ortho-carbon and eventually leads to a loss of a halogen and GSH replacement. The initial step of GSH addition at the ipso position is also supported by density functional theory, which suggests that the ipso carbon of the chloro, bromo, and iodo (but not fluoro) containing 2-fluoro-4-haloanilines is the most positive carbon and that these molecules have the favorable highest occupied molecular orbital of the aniline and the lowest unoccupied orbital from GSH. The para-substituted halogen (chloro, bromo, or iodo but not fluoro) played a pivotal role in the formation of the QX, which required a delocalization of the positive charge on the para-halogen after oxidation. This mechanism was supported by structure-metabolism relationship analysis of a series of dihalogenated and monohalogenated aniline analogues.     

Comparative molecular field analysis of some clodronic acid esters.

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate three different types of biological activity data with physicochemical properties of some clodronate ester analogues, which act as bone-resorption regulators in cell cultures and rats. The QSAR studies show the importance of the steric properties of these new bisphosphonate derivatives for the inhibition of bone resorption in bone cell cultures and for their bioavailability in rats. This information will be used in predicting the structure of new more potent bisphosphonic compounds.