A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes

A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 of the 25 antagonists were fitted to the model in a low energy conformation with a low RMS value. The pharmacophore model is described by four pharmacophore elements: Three hydrophobic groups and a hydrogen bond donor represented as a vector. The hydrophobic groups are generally aromatic rings, but this is not a requirement. The antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. The model was able to explain the enantioselectivity of SR48968 and GR159897.     

基于结构和药效团特征的人类腺苷受体拮抗剂选择性比较

腺苷受体是重要的治疗靶标,选择性腺苷受体拮抗剂具有广泛的临床应用前景.本文通过同源模建构建了腺苷A₁、A_2B和A₃受体的结构,采用LigandScout 3.12软件分别构建了腺苷受体四种亚型的拮抗剂药效团模型.然后利用Schrödinger程序中的Induced Fit Docking模块完成受体-拮抗剂结合模式的预测,并与药效团结果进行比对.结果发现,由于结合口袋部位的残基在家族间高度保守,模建得到的各个亚型受体的初始结构活性口袋部位极为相似,无法用于亚型选择性拮抗剂的识别.而腺苷受体四种亚型拮抗剂药效团的药效特征与空间排布都不同,并与以前突变实验信息相吻合.研究结果说明,结合口袋部位的优化是模建中的关键步骤,基于配体的药效团模型所包含的一系列药效特征元素如氢键受体、氢键供体、疏水基团、芳环中心,可以很好地表征受体结合部位氢键、疏水空腔的位置及其方向.本文研究结果可以为进一步的优化同源模建结果,寻找新型的人类腺苷受体选择性拮抗剂提供理论依据.     

3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists

Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.     

Comparative pharmacophore modeling of human adenosine receptor A1 and A3 antagonists

Adenosine receptors are promising therapeutic targets in drug discovery. In this study, three-dimensional pharmacophore models of human adenosine receptor A1 and A3 antagonists were developed based on 26 and 23 diverse compounds, respectively. The best A1 pharmacophore model (A 1 _Hopy1) consists of four features: one hydrogen bond donor, one hydrophobic point and two ring aromatics, while the best A 3 pharmacophore model (A3 _Hopy1) also has four features: one hydrogen bond acceptor, one hydrophobic point and two ring aromatics. The correlation coefficients were 0.840 for A 1 test set with 146 diverse compounds and 0.827 for A3 test set with 238 diverse compounds. In the simulated virtual screening experiments, high enrichment factors of 6.51 and 6.90 were obtained for A 1 _Hopy1 and A3 _Hopy1 models, respectively. Moreover, two models also showed high subtype-selectivity in the simulated virtual screening experiments. These results could be helpful for the discovery of novel potent and selective A 1 and A3 antagonists.     

Identification of new dual spleen tyrosine kinase (Syk) and phosphoionositide-3-kinase δ (PI3Kδ) inhibitors using ligand and structure-based integrated ideal pharmacophore models

Owing to the complex pathophysiology of autoimmune disorders, it is very challenging to develop successful treatment strategies. Single-target agents are not desired therapeutics for such multi-factorial disorders. Considering the current need for the treatment of complex autoimmune disorders, dual inhibitors of Syk and PI3Kδ have been designed using ligand and structure-based molecular modelling strategies. In the present work, structure and ligand-based pharmacophore modelling was implemented for a varied set of Syk and PI3Kδ inhibitors. Ligand-based pharmacophore models (LBPMs) were developed for two kinases: ADPR.14 (r²_train = 0.809) for Syk, comprising one hydrogen bond acceptor, one hydrogen bond donor, one positive ionisable and one ring aromatic feature, and for PI3Kδ: AAARR.45 (r²_train = 0.942) consisting of three hydrogen bond acceptor and two ring aromatic features. The generated e-pharmacophore models revealed an additional ring aromatic and hydrophobic feature important for Syk and PI3Kδ inhibition, respectively. Subsequently, LBPMs were modified resulting in APDRR.14 hypothesis for Syk inhibitors and AAAHRR.45 hypothesis for PI3Kδ inhibitors employed for virtual screening. Thus, the combination of ligand and structure-based pharmacophore modelling helped in developing ideal pharmacophore models that may be an efficient tool for the designing of novel dual inhibitors of Syk and PI3Kδ.     

Pharmacophore-based structure optimization of angiotensin converting enzyme inhibitory peptide

Chemical feature based pharmacophore models were generated for an angiotensin converting enzyme(ACE) inhibitory peptide using the Discovery Studio 2.0 pharmacophore modeling approach. The pharmacophore hypothesis selected has five features(one negative ionizable region,one hydrogen bond donor,one hydrogen bond acceptor and two hydrophobic functional groups). Additionally,ACE inhibitory hexapeptide previously obtained from silkworm pupae protein was optimized to target the ACE based on the selected pharmacophore. The results suggest that tri-peptide(thr-val-phe) may be structural determinant of ACE activity. Docking studies further provided confidence for the validity of the selected pharmacophore model to perform structure optimization of the ACE inhibitory peptide.     

Pharmacophore modeling as an efficient tool in the discovery of novel noncompetitive AMPA receptor antagonists

A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonists was developed in order to map common structural features of highly active compounds. This hypothesis, which consists of two hydrophobic regions, one hydrogen bond acceptor and one aromatic region, was successfully used as framework for the design of a new class of allosteric modulators containing a tetrahydroisoquinoline skeleton and for in silico screening. The promising biological results suggested that the identified molecules might be useful "lead compounds" for future drug development.     

Conformational analyses on histamine H2-receptor antagonists

Summary In a series of compounds with H₂-antihistaminic activity, a conformational analysis was performed based on force field calculations. The drugs studied were cimetidine, ranitidine, famotidine, roxatidine and the conformationally more restricted ICI127032. For the compounds containing a flexible chain, the local minima conformations and the global minimum conformation were calculated. These conformations were used for a systematic structural comparison with all energetically allowed conformations of the ICI derivative, with regard to the best fit of the common structural features. In this way a pharmacophore could be developed consisting of four parts: (1) a polar planar group, uncharged at physiological pH; (2) a hydrophobic part formed by aromatic systems or flexible chains; (3) an—under physiological conditions—protonated nitrogen atom; and (4) a substructure, which contains a hydrogen bond donor site and a hydrogen bond acceptor site in a specific spatial arrangement.     

大麻素Ⅰ型受体拮抗剂的结构特征

以92个具有大麻素受体Ⅰ(CB1)拮抗活性的化合物为训练集, 39个化合物为测试集, 采用Discovery Studio V2.5(DS)软件中的3D构效关系药效团产生(QSAR Pharmacophore Generation)模块建立药效团模型. 获得的最佳药效团模型的构成为一个氢键受体(HBA)、 一个疏水基团(HY)和二个芳环中心(RA), 采用费用函数(Cost function)评价药效团模型, 该模型的Δcost为119.32, 相关性为0.921, 均方根偏差为0.730, Configuration cost为16.1229, 表明模型能较好地预测化合物的活性. 同时针对目前已知的近450个化合物的12种结构类型进行了探讨, 所得结果为进一步设计CB1拮抗剂提供了理论依据.     

Molecular modelling studies on adamantane-based Ebola virus GP-1 inhibitors using docking,pharmacophore and 3D-QSAR

The pathogenic Ebola virus (EBOV) causes a potential health risk and global spread. To date, few drugs are available for the treatment of Ebola virus disease (EVD) that allow researchers to use computational methods for designing potential drugs. The developed PHASE-based common six-point pharmacophore hypothesis (AADHPR_1) showed the necessity of two hydrogen bond acceptor features, one hydrogen bond donor feature, one hydrophobic group feature, one positively ionizable and one aromatic ring feature for further designing. We developed best 3D-QSAR models with high regression coefficients for the training (r²>0.82) and test (Q²>0.5) sets for both atoms-based and field-based 3D-QSAR models. The molecule 1A-4 (docking score = –4.711 kcal/mol) was obtained as best docked (SP mode) on Ebola virus envelope glycoprotein (PDB ID-3CSY) as compared with the standards oseltamivir (docking score = –4.39 kcal/mol) and zanamivir (docking score = –3.392 kcal/mol). The obtained ZINC hit ZINC58935541 showed a good docking score of –4.892 kcal/mol. The ZINC58935541 molecule also showed a strong binding affinity towards the receptor cavity of Ebola virus envelope glycoprotein when simulated for 1.2 ns. The good QikProp parameters reflect the fact that this molecule, upon optimization into a lead, might become a good candidate for the treatment of EVD.     

Influence of the conditions in pharmacophore generation, scoring, and 3D database search for chemical feature-based pharmacophore models: one application study of ETA- and ETB-selective antagonists

Using the commercial pharmacophore modeling suite Catalyst, we have studied the influence of the compare.scaledMultiBlobFeatureErrors . Catalyst parameter. The influence of this parameter has been studied in pharmacophore generation, hypothesis scoring, and database searching. This parameter, introduced in Catalyst 4.7, changed its default value in Catalyst 4.8, and it strongly influences the statistical quality of pharmacophore generation, scoring of the hypotheses, and database searching. Two different pharmacophore models have been constructed for the ETA and ETB receptor antagonists. Both models contain one positive ionizable, one negative ionizable, one hydrogen-bond acceptor, one hydrophobic aromatic, and one hydrophobic aliphatic feature. The models have been compared, and some differences in the position of the hydrogen-bond acceptor in the putative binding pocket have been highlighted.     

表皮生长因子受体酪氨酸激酶抑制剂的药效团研究

根据一系列表皮生长因子受体酪氨酸激酶抑制剂的三维定量构效关系研究，得 到了该类抑制剂的药效团，研究结果与Novartis的药效团模型相当类似．药效团包 括一个氢键受体，一个氢键给体，一个疏水区和一个带有氯或溴原子药效团对于研 究表皮生长因子受体酪氨酸激酶抑制剂结构与活性的关系具有重要的意义．通过三 维数据库搜索可能会得到新的先导化合物．     

Liquid chromatographic studies on the aqueous solution conformation of substituted benzamide drug models

The aqueous solution conformation of a series of model benzamides related to the orthopramide dopamine receptor antagonists is evaluated by reversed-phase liquid chromatography (LC). The structure-retention relationship studies demonstrate the existence of an intramolecular hydrogen bond formed in aqueous solution for these compounds. The six-membered pseudoring formed by the association of the amide N-H and the oxygen of the 2-methoxy group (N-H...O) produces enhanced reversed-phase retention (increased capacity factors, k') relative to the 3- and 4-isomers. Deletion of either the acceptor oxygen or the donor N-H results in decreased C18 retention of the 2-isomer relative to the 3- and 4-isomers. These structure-retention relationship studies reveal the value of reversed-phase LC methods for evaluation of the aqueous solution conformation of the orthopramide-type compounds. Further studies show that N-substituted 2-hydroxybenzamides are intramolecularly associated in aqueous solution through either N-H...O or O-H...O six-membered rings. The 6-methoxysalicylamides are believed to be stabilized through O-H to carbonyl oxygen bonding in addition to the N-H...O pseudoring. For the 2,6-dimethoxybenzamides, steric factors prevent methoxy-amide coplanarity, thus no intramolecular hydrogen bond is formed. The result is a dramatic decrease in retention for the 2,6-isomer relative to the other positional isomers. These studies suggest that remoxipride and related 2,6-dimethoxybenzamides cannot form the six-membered pseudoring believed to be topographically equivalent to the aromatic ring in dopamine.     

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH₂) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH₂ (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.     

β分泌酶抑制剂的药效团模型研究

选择活性跨越0.002至25 μmol•L－1的4类共25个β分泌酶抑制剂作为训练集, 使用Catalyst软件包构建出药效团模型, 并通过对药效团的有效性分析, 筛选得到的最佳模型(correlCorrel＝0.969, Config＝16.32, Δcost＝62.422)由一个环芳香性、一个疏水中心、一个正电荷中心和一个氢键供体组成. 并用其它209个抑制剂组成测试集对模型进行验证, 结果表明该模型显示出较强的预测能力, 能够为进一步的数据库搜索, 寻找新型的β分泌酶抑制剂先导物提供依据.     

Molecular dynamics and pharmacophore modelling studies of different subtype (ALK and EGFR (T790M)) inhibitors in NSCLC

Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r² = 0.96, q² = 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r² = 0.92, q² = 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M). These pharmacophore models allowed searches for novel ALK and EGFR (T790M) dual inhibitors from multiconformer 3D databases (Asinex, Chembridge and Maybridge). Finally, the eight best hits were selected for molecular dynamics simulation, to study the stability of their complexes with both proteins and final binding orientations of these molecules. After molecular dynamics simulations, one hit has been predicted to possess good binding affinity for both ALK and EGFR (T790M), which can be further investigated for its experimental in-vitro/in-vivo activities.     

促生长激素释放素三维定量构效关系及药效团模型

用比较分子场分析方法对促生长激素释放素Ｌ－６９２，４２９的系列物进行了三维定量构效研究，得到具有较强预测能力的模型并确定了母体的活性构象，用距离比较方法将Ｌ－６９２，４２９的活性构象与两个活性多肽进行了迭合，找到了可能的药效团，药效团模型显示Ｌ－６９２，４２９的氨基和四唑是氢键的给体和受体，而Ａ和Ｃ环是主要的疏水核心。     

Ligand-based molecular modeling study on a chemically diverse series of cholecystokinin-B/gastrin receptor antagonists: generation of predictive model

Pharmacophore hypotheses were developed for six structurally diverse series of cholecystokinin-B/gastrin receptor (CCK-BR) antagonists. A training set consisting of 33 compounds was carefully selected. The activity spread of the training set molecules was from 0.1 to 2100 nM. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, two hydrogen bond donors, one hydrophobic aliphatic, and one hydrophobic aromatic feature, had a correlation (r) of 0.884 and a root-mean-square deviation of 1.1526, and the cost difference between null cost and fixed cost was 81.5 bits. The model was validated on a test set consisting of six different series of 27 structurally diverse compounds and performed well in classifying active and inactive molecules correctly. This validation approach provides confidence in the utility of the predictive pharmacophore model developed in this work as a 3D query tool in the virtual screening of drug-like molecules to retrieve new chemical entities as potent CCK-BR antagonists. The model can also be used to predict the biological activities of compounds prior to their costly and time-consuming synthesis.     

A genetic algorithm for flexible molecular overlay and pharmacophore elucidation

Summary A genetic algorithm (GA) has been developed for the superimposition of sets of flexible molecules. Molecules are represented by a chromosome that encodes angles of rotation about flexible bonds and mappings between hydrogen-bond donor proton, acceptor lone pair and ring centre features in pairs of molecules. The molecule with the smallest number of features in the data set is used as a template, onto which the remaining molecules are fitted with the objective of maximising structural equivalences. The fitness function of the GA is a weighted combination of: (i) the number and the similarity of the features that have been overlaid in this way; (ii) the volume integral of the overlay; and (iii) the van der Waals energy of the molecular conformations defined by the torsion angles encoded in the chromosomes. The algorithm has been applied to a number of pharmacophore elucidation problems, i.e., angiotensin II receptor antagonists, Leu-enkephalin and a hybrid morphine molecule, 5-HT_1D agonists, benzodiazepine receptor ligands, 5-HT₃ antagonists, dopamine D₂ antagonists, dopamine reuptake blockers and FKBP12 ligands. The resulting pharmacophores are generated rapidly and are in good agreement with those derived from alternative means.     

Interplay between hydrogen bond formation and multicenter pi-electron delocalization: intermolecular hydrogen bonds

The interplay between aromatic electron delocalization and intermolecular hydrogen bonding is thoroughly investigated using multicenter delocalization analysis. The effect on the hydrogen bond strength of aromatic electron delocalization within the acceptor and donor molecules is determined by means of the interaction energies between monomers, calculated at the B3LYP/6-311++G(d,p) level of theory. This magnitude is compared to variations of multicenter electron delocalization indices and covalent hydrogen bond indices, which are shown to correlate perfectly with the relative values of the interaction energies for the different complexes studied. The multicenter electron delocalization indices and covalent bond indices have been computed using the quantum theory of atoms in molecules approach. All the hydrogen bonds are formed with oxygen as the acceptor atom; however, the atom bonded to the donor hydrogen has been either oxygen or nitrogen. The water-water complex is taken as reference, where the donor and acceptor molecular environments are modified by substituting the hydrogens and the hydroxyl group by phenol, furan, and pyrrole aromatic rings. The results here shown match perfectly with the qualitative expectations derived from the resonance model.