3-D QSAR for intrinsic activity of 5-HT1A receptor ligands by the method of comparative molecular field analysis

The affinity of a ligand for a receptor is usually expressed in terms of the dissociation constant (K_i) of the drug-receptor complex, conveniently measured by the inhibition of radioligand binding. However, a ligand can be an antagonist, a partial agonist, or a full agonist, a property largely independent of its receptor affinity. This property can be quantitated as intrinsic activity (1A), which can range from 0 for a full antagonist to 1 for a full agonist. Although quantitative structure–activity relationship (QSAR) methods have been applied to the prediction of receptor affinity with considerable success, the prediction of IA, even qualitatively, has rarely been attempted. Because most traditional QSAR methods are limited to congeneric series, and there are often major structural differences between agonists and antagonists, this lack of success in predicting IA is understandable. To overcome this limitation, we used the method of comparative molecular field analysis (CoMFA), which, unlike traditional Hansch analysis, permits the inclusion of structurally dissimilar compounds in a single QSAR model. A structurally diverse set of 5-hydroxytryptamine_1A (5-HT_1A) receptor ligands, with literature IA data (determined by the inhibition of 5-HT sensitive forskolin-stimulated adenylate cyclase), was used to develop a 3-D QSAR model correlating intrinsic activity with molecular structure properties of 5HT_1A receptor ligands. This CoMFA model had a crossvalidated r² of 0.481, five components and final conventional r² of 0.943. The receptor model suggests that agonist and antagonist ligands can share parts of a common binding site on the receptor, with a primary agonist binding region that is also occupied by antagonists and a secondary binding site accommodating the excess bulk present in the sidechains of many antagonists and partial agonists. The CoMFA steric field graph clearly shows that agonists tend to be “flatter” (more coplanar) than antagonists, consistent with the difference between the 5-HT_1A agonist and antagonist pharmacophores proposed by Hibert and coworkers. The CoMFA electrostatic field graph suggests that, in the region surrounding the essential protonated aliphatic amino group, the positive molecular electrostatic potential may be weaker in antagonists as compared to agonists. Together, the steric and electrostatic maps suggest that in the secondary binding site region increased hydrophobic binding may enhance antagonist activity. These results demonstrate that CoMFA is capable of generating a statistically crossvalidated 3-D QSAR model that can successfully distinguish between agonist and antagonist 5-HT_1A ligands. To the best of our knowledge, this is the first time this or any other QSAR method has been successfully applied to the correlation of structure with IA rather than potency or affinity. The analysis has suggested various structural features associated with agonist and antagonist behaviors of 5-HT_1A ligands and thus should assist in the future design of drugs that act via 5-HT_1A receptors. © 1993 John Wiley & Sons, Inc.     

Molecular Docking and 3D QSAR Research of Indolocarbazole Series as Cyclin-Dependent Kinase Inhibitors

Fifty indolocarbazole series as cyclin-dependent kinase inhibitors (CDKs) are used to establish a threedimensional quantitative structure-activity relationship (3D QSAR) model based on docking conformations resulting from the Topomer comparative molecular field analysis (Topomer CoMFA). The statistic parameters show that the cross-validation (q²), the multiple correlation coefficient of fitting (r²), and external validation statistic (Q_ext²) are 0.953, 0.968, and 0.954, respectively. It is demonstrated that this Topomer CoMFA model has good stability and prediction ability. The methodology of the fragment-based drug design (FBDD) was also used to virtually screen new CDKs by the Topomer Search technology. Four similar substitutional groups selected from the ZINC database were added to the basic scaffold. As a result, 18 new CDKs with high activities were obtained. The template molecule and new designed compounds are used to study the binding relationship between the ligands and the receptor protein with Surflex-Dock. The docking results suggest good binding interactions of the designed compounds with protein. There are several hydrogen bondings between CDKs with amino acid residues of LYS33, LYS89, ASP86, LEU83, GLU81.     

Three-dimensional Quantitative Structure-Activity Relationship Analyses of a Series of Butenolide ETA Antagonists

Two kinds of Three-dimensional Quantitative Structure-activity Relationship(3D-QSAR) methods,comparative molecular filed analysis(CoMFA) and comparative molecular similarity indices analysis (CoMSIA) ,were applied to analyze the structure-activity relationship of a series of 63 butenolide ETA selective antagonists with respect to their inhibition against human ETA receptor,The CoMFA and CoMSIA models were developed for the conceivable alignment of the molecules based on a template structure from the crystallized data.The statistical results from the initial orientation of the aligned molecules show that the 3D-QSAR model from CoMFA(q^2=0.543) is obviously superior to that from the conventional CoMSIA(q^2=0.407).In order to refine the model,all-space search (ASS) was applied to minimize the field sampling process.By rotating and translating the molecular aggregate within the grid systematically,all the possible samplings of the molecular fields were tested and subsequently the one with the highest q^2 was picked out .The comparison of the sensitivity of CoMFA and CoMSIA to different space orientation shows that the CoMFA q^2 values are more sensitive to the translations and rotations of the aligned molecules with respect to the lattice than those of CoMSIA.The best CoMFA model from ASS was further refined by the region focused technique.The high quality of the best model is indicated by the high corss-validated correlation and the prediction on the external test set.The CoMFA coefficient contour plots identify several key features that explain the wide range of activities,which may help us to design new effective ETA selective antagonists.     

培氟沙星均三唑硫醚衍生物抗肝癌活性的CoMFA模型与分子设计

基于比较分子力场分析(CoMFA)方法建立24种培氟沙星均三唑硫醚衍生物抗肝癌活性(pM)的三维定量构效关系(3D-QSAR)。训练集中20个化合物用于建立预测模型,测试集10个化合物(含模板分子及新设计的5个分子)作为模型验证。已建立的3D-QSAR模型的交叉验证系数(R_cv²)、非交叉验证系数(R^₂)分别为0.705、0.940,说明所建模型具有较强的稳定性和良好的预测能力。该模型中立体场、静电场贡献率依次为74.8%、25.2%,表明影响抗肝癌活性(pM)的主要因素是取代基的疏水性和空间契合,其次是库仑力、氢键及配位。基于三维等势图,设计了5个具有较高抗肝癌活性的分子,有待医学实验验证。     

Evaluation of 1‐arylpiperazine derivative of hydroxybenzamides as 5‐HT1A and 5‐HT7 serotonin receptor ligands: An experimental and molecular modeling approach

The synthesis and evaluation as 5‐HT_1A and 5‐HT₇ serotonin receptor ligands of the two sets of O‐substituted hydroxybenzamides, structurally related to 2‐{3‐[4‐(2‐methoxyphenyl)piperazin‐1‐yl]propoxy}benzamide ( 1 ), (K_i 5‐HT_1A = 21 nM, 5‐HT₇ = 234 nM) are reported. To affect the affinity for 5‐HT_1A and 5‐HT₇ receptors, an amide moiety ( 2 , 3 , 4 , 5 , 6 ) and a hydrocarbon chain length ( 7 , 8 , 9 , 10 ) were modified. The serotonergic activity of compounds 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 was generally higher in the case of 5‐HT_1A receptors compared with 5‐HT₇ ones; the most active 5‐HT_1A ligands being meta‐isomer 2 (K_i = 7 nM) and both analogs of 1 with the longest spacer, i.e., penta‐ and hexa‐methylene derivatives 9 and 10 (K_i = 4 and 3 nM, respectively). The observed biological properties of compounds 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 were elucidated using molecular modeling procedures. J. Heterocyclic Chem., (2010).     

Comparative QSAR studies using HQSAR,CoMFA, and CoMSIA methods on cyclic sulfone hydroxyethylamines as BACE1 inhibitors

The inhibition of β-secretase (BACE1) is currently the main pharmacological strategy available for Alzheimer’s disease (AD). 2D QSAR and 3D QSAR analysis on some cyclic sulfone hydroxyethylamines inhibitors against β-secretase (IC₅₀: 0.002–2.75 μM) were carried out using hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) methods. The best model based on the training set was generated with a HQSAR q² value of 0.693 and r² value of 0.981; a CoMFA q² value of 0.534 and r² value of 0.913; and a CoMSIA q² value of 0.512 and r² value of 0.973. In order to gain further understand of the vital interactions between cyclic sulfone hydroxyethylamines and the protease, the analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the BACE1. The final QSAR models could be helpful in the design and development of novel active BACE1 inhibitors.     

QSAR models of cytochrome P450 enzyme 1A2 inhibitors using CoMFA,CoMSIA and HQSAR

Quantitative structure–activity relationship (QSAR) studies were conducted on an in-house database of cytochrome P450 enzyme 1A2 inhibitors using the comparative molecular field analysis (CoMFA), comparative molecular similarity analysis (CoMSIA) and hologram QSAR (HQSAR) approaches. The database consisted of 36 active molecules featuring varied core structures. The model based on the naphthalene substructure alignment incorporating 19 molecules yielded the best model with a CoMFA cross validation value q² of 0.667 and a Pearson correlation coefficient r² of 0.976; a CoMSIA q² value of 0.616 and r² value of 0.985; and a HQSAR q² value of 0.652 and r² value of 0.917. A second model incorporating 34 molecules aligned using the benzene substructure yielded an acceptable CoMFA model with q² value of 0.5 and r² value of 0.991. Depending on the core structure of the molecule under consideration, new CYP1A2 inhibitors will be designed based on the results from these models.     

QSAR and 3D-QSAR studies of the diacyl-hydrazine derivatives containing furan rings based on the density functional theory

QSAR studies of 27 diacyl-hydrazine derivatives containing furan rings were conducted and compared with the DFT method and AM1-MOPAC method. q ² values of 0.61 and 0.40 validated the predictability and reliability of eq. (5) from the DFT method were higher than those of eq. (6) from the AM1-MOPAC method. The DFT-optimized conformations and ESP-fitting charges of the target compounds were also used for 3D-QSAR analysis, including CoMFA and CoMSIA. The leave-one-out cross-validation correlation coefficient and the good correlation between the predicted and experimental activities of excluded test compounds revealed that CoMFA and CoMSIA models were robust. The QSAR results were consistent with the 3D-QSAR results, indicating that the electrostatic and hydrophobic properties of the target compounds were significant to the biological activity. These models are useful tools for predicting the larvicidal activities of new compounds and designing new specific insect growth regulators.     

Receptor-based 3D QSAR analysis of estrogen receptor ligands – merging the accuracy of receptor-based alignments with the computational efficiency of ligand-based methods

One of the major challenges in computational approaches to drug design is the accurate prediction of binding affinity of biomolecules. In the present study several prediction methods for a published set of estrogen receptor ligands are investigated and compared. The binding modes of 30 ligands were determined using the docking program AutoDock and were compared with available X-ray structures of estrogen receptor-ligand complexes. On the basis of the docking results an interaction energy-based model, which uses the information of the whole ligand-receptor complex, was generated. Several parameters were modified in order to analyze their influence onto the correlation between binding affinities and calculated ligand-receptor interaction energies. The highest correlation coefficient (r ² = 0.617, q ² _LOO = 0.570) was obtained considering protein flexibility during the interaction energy evaluation. The second prediction method uses a combination of receptor-based and 3D quantitative structure-activity relationships (3D QSAR) methods. The ligand alignment obtained from the docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection, a significant and robust model was obtained (r ² = 0.991, q ² _LOO = 0.921). The predictive ability of the established model was further evaluated by using a test set of six additional compounds. The comparison with the generated interaction energy-based model and with a traditional CoMFA model obtained using a ligand-based alignment (r ² = 0.951, q ² _LOO = 0.796) indicates that the combination of receptor-based and 3D QSAR methods is able to improve the quality of the underlying model.     

Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

Summary Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/K_i), with an explained variance r² of 0.885, and a cross-validated q² of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q² for one component was 0.62 and 0.61, respectively, while r² was 0.674. We demonstrate that the predictive r² based on the mean activity (Y_m) of the training set is misleading, while the test set Y_m-based predictive r² index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.     

The synthesis of cyclic and acyclic long‐chain arylpiperazine derivatives of salicylamide as serotonin receptor ligands

The 1‐arylpiperazine series of N‐substituted 1,3‐benzoxazine‐2,4‐diones as well as O‐ and N‐substituted salicylamides with an n‐propyl chain were synthesized in order to explore the effect of cyclic and acyclic salicylamide moieties on their binding affinity for 5‐HT_1A, 5‐HT_2A and 5‐HT₇ receptor sites. Target compounds 1 and 2 were prepared by a two‐step procedure, i.e. by alkylation of 1,3‐benzoxazine‐2,4‐dione or salicylamide with 1,3‐dibromopropane and next by condensation of 3‐bromopropyl intermediates with arylpiperazines; syntheses of 3‐bromopropyl intermediates were performed in solvent‐free conditions. Compounds 3 were prepared by hydrolysis of 1 . In respect of salicylamide moieties, binding affinities for 5‐HT_1A and 5‐HT₇ receptors increase according to the rank of derivatives 3 < 1 < 2 , for the same arylpiperazines. Regarding 5‐HT_2A receptors, increased activity of ligands was changed in reverse order to the affinity for 5‐HT_1A, i.e. 2 < 1 < 3 . 5‐HT_1A and 5‐HT₇ receptor binding constants were the highest for the 2‐methoxyphenyl ligand 2c , while the 3‐chlorophenyl ligand 3b was most active for 5‐HT_2A receptors.     

QSAR of conformationally flexible molecules: Comparative Molecular Field Analysis of protein-tyrosine kinase inhibitors

Summary Comparative Molecular Field Analysis (CoMFA) has been applied to a study of quantitative structureactivity relationships (QSAR) of conformationally flexible molecules. The relationship between three-dimensional structure and activity of 20 styrene derivatives which inhibit protein-tyrosine kinase was determined. A technique was developed that allows accurate prediction of the inhibitory activity of these molecules and identification in each case of the active conformation. The problem of multiple energetically acceptable conformations was approached in an iterative procedure. Use was made of the varying degrees of symmetry among the molecules. First, CoMFA QSAR models were developed using only those compounds that possess a symmetrical substituent pattern on the phenyl ring. These CoMFA models were then used to select the active conformers of the less symmetrical compounds in the set. Allowing multiple conformers for each compound in the dataset yielded higher crossvalidated r² values and better predictivity of the QSAR models. Different probe atoms (C⁺, O^–, neutral C) were explored, the O^– probe atom exhibiting the highest selectivity in the conformer selection process.     

Synthesis and biological testing of 3‐phenyloctahydro‐pyrimido[1,2‐a]‐s‐triazine derivatives

A series of 46 3‐phenyloctahydropyrimido[1,2‐a]‐s–triazine derivatives were synthesized. This synthesis was performed via iminodimethylation of dialkylated 2‐aminopyrimidinedione synthons by substituted primary arylamines. In vitro pharmacological evaluation of these compounds is reported. One of them exhibited antifungal activity against Microsporum canis (10^?6₅₀10^?5 mol/L), and another showed affinity for serotoninergic 5‐HT_1A and 5‐HT_2b receptors (10^?8₅₀10^?7 mol/L).     

Synthesis of hydroxy- and methoxy-substituted octahydrobenzo[g]isoquinolines as potential ligands for serotonin receptors

In 7 steps, 6- or 9-hydroxylated or -methoxylated trans-octahydrobenzo[g]isoquinolines were efficiently synthesized starling from dimethoxynaphtbalenes (Scheme), as potential new selective ligands for serotonin receptors. The 6-substituted compounds had very little affinity to common neurotransmitter receptors, with the exception of adrenergic α₂. The 9-substituted compounds, while showing interesting affinity for 5HT_1a receptors, had comparable affinities for adrenergic α₁ and β₂, and in one case for dopamine D2 receptors.