Conformation of 1,4-dihydropyridine calcium channel blockers and H-bonds in a crystal

A statistical analysis of conformations for flexible 1,4-dihydropyridine calcium channel blockers, which are derivatives of nifedipine, was performed on the basis of the data deposited with the Cambridge Crystallographic Data Centre. Inequality of N and C deviations from the root-mean-square plane of the heterocycle was verified. A correlation was established between the orientation of carbonyls and their ability to form H-bonds in a crystal.     

Phenylalkylamines as calcium channel blockers

In this study we present ab initio Hartree Fock molecular orbital calculations with complete geometry optimizations on some phenylalkylamines (PAAs) that are clinically used as antiarrhythmic drugs. Pharmacophoric features of PAAs have been derived. An explanation of potency regulation in PAAs has been suggested based on ion capturing vs. ion holding by the drug. Ion capturing by the drug is always electrostatically highly favourable but has to be analysed in terms of conformational changes required and physiological accessibility of the situation. Our results also seem to offer an explanation for inhibitory effect of Ca²⁺ ion concentration on binding affinity of PAAs.     

On-selective electrodes for some β-adrenergic and calcium blockers

Potentiometric sensors based on dinonylnaphthalene sulfonic acid (DNNS) were prepared for several recently developed drugs used in the treatment of cardiovascular disorders. Thus, incorporation of DNNS along with the β-adrenergic blocker Acebutalol, or calcium-channel blockers Verapamil, Diltiazem, Nicardipine, or Lidoflazine into a plasticized poly(vinyl chloride) membrane resulted in coated-wire ion-selective electrodes which displayed nearly Nernstian response in the concentration range 10^?3–10^?5 M and quantitatively useful responses down to 10^?6 M. Selectivity behavior for each set of electrodes was accurately predicted from calculated distribution constants for the respective drugs. Application of these electrodes to pharmaceutical preparations is discussed, as is their utility in pharmacokinetic studies.     

Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

Summary Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxylate], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5-carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxylate] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within ± 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca²⁺ channel and its ability to accommodate both antagonist and activator ligands.     

QSAR modeling and chemical space analysis of antimalarial compounds

Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.     

Analysis of dihydropyridine calcium channel blockers using negative ion photoionization mass spectrometry

The fragmentation of dihydropyridine calcium-channel antagonists are compared by electrospray ionization (ESI) and atmospheric pressure photonization (APPI). The results demonstrate that in ESI the preferred ionization process is in positive mode, with the mass spectra of [M+H]+ showing base peak ions probably formed by loss of alcohols from carboxyl groups. Conversely, in APPI, a high intense peak is observed in negative mode due to deprotonated molecule [M-H]- after two serial 1, 2-hydride shifts leading to a rearranged deprotonated molecule [M-H]-. These ions undergo another 1,2-hydride shifts to produce a nitro-phenyl product ion of m/z 122. The APPI is also used to develop a method for the quantitation of dihydropyridines (e.g., nifedipine) in human plasma.     

Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors

In an attempt to rationalize the search for new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines the prediction of physicochemical and pharmacokinetic properties, molecular docking, molecular dynamic simulation, and free energy calculation. Starting from a small library of compounds synthesized previously, it was found that 70% of the compounds analyzed satisfy with the associated values to physicochemical principles as key evaluation parameters for the drug-likeness; all the compounds presented good gastrointestinal absorption and cerebral permeability and they showed an interaction with the Arg 106 residue of the COX-2 isoenzyme. Finally, it was obtained that compound 3ab has a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug celecoxib, suggesting that this compound could become a powerful candidate in the inhibition of the COX-2 enzyme. In addition, we realized the crystallographic analysis of compounds 3j, 3r, and 3t defining the crystal parameters and the Packing interactions.     

维甲化合物与维甲X受体相互作用模拟及QSAR研究

用分子对接确定了一系列RXR激动剂与受体的作用方式,与X衍射测得的晶体复合物中9-cis-RA的作用方式相近。对接后的配体-受体复和物经分子力学优化后更接近药效构象,两者相互作用能与活性具有一定的相关性,相关系数R^2=0.64。用活性构象建立的CoMFA模型比低能构象建立的CoMFA模型有更高的可信度,其交叉验证相关系q^2=0.791,非交叉验证相关系数γ^2=0.988,绝对误差SE=0.099,f6,33=456.8。     

Comparative molecular modelling study of the calcium channel blockers nifedipine and black mamba toxin FS2

The identification and structural determination of the criticalamino acid residues causing the calcium channel blocking effects of theangusticeps type III toxin FS₂ is described. Alignments withmore than 200 different short and long neuro-, cyto-, muscarinic and otherangusticeps-type toxins yielded 12 amino acid residues at the tips of loopsII and III which are unique to the type III toxins. The competitive bindingbehaviour between the 1,4-dihydropyridine derivative nifedipine and toxinFS₂ was used for a further delimitation of the relevant toxinbinding domain. Using the ab initio geometry optimized nifedipine X-raystructure as a template, a model based on the sequenceMet⁴⁵-Trp⁴⁶-cis-Pro⁴⁷-Tyr⁴⁸has been elaborated. This sequence shows the same hydrophobic andhydrogen bond forming properties as nifedipine. In addition, qualitativelysimilar molecular electrostatic potentials are observed for both structures,leading to the assumption that these amino acid residues of the toxin act asthe potential attachment region at the calcium channel receptor site.     

Simultaneous determination of chloroquine and selected calcium(II) channel blockers by high-performance liquid chromatography

Chloroquine (CQ), which is the primary drug for treatment and prophylaxis against malaria, has become ineffective because of the high prevalence of CQ-resistant P. falciparum parasites, but resistant parasites exposed to a Ca(II) channel blocker become as susceptible to CQ as sensitive parasites. A reversed-phase liquid chromatographic method is described for simultaneously determining CQ, its metabolites desethyl-CQ and bisdesethyl-CQ, the Ca(II) channel blocker verapamil, and the tiapamil analogue N-(3,4-dimethoxyphenethyl)- N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride. The analytes were separated by gradient elution with acetonitrile and 1-heptane sulfonic acid; the detector wavelength was 232 nm. The mean recovery from spiked plasma was 100.1 ± 2.28 (SD). Within-day retention times were reproducible to within ± 0.03 SD of mean values and the lower limit of detection was about 2 ng of each analyte.     

Conformational flexibility of the 1,4-dihydropyridine ring in calcium channel agonists and antagonists molecules

Conformational flexibility of the 1,4-dihydropyridine ring in 4-aryl derivatives of the 2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine has been studied using the MM3 molecular mechanics method. Change of the C=C---C---C= endocyclic torsion angle of dihydrocycle in the range of 35° entails an increase of energy less than 1 kcal mol⁻¹. The energy levels below 99% of the molecular population for each molecule were estimated. The interval of the torsion angle change for these regions is about 60°.     

Synthesis of some pyrimido[4,5-b][1,4]oxazines starting from 5-aminopyrimidines

Derivatives of pyrimido[4,5-b] [1,4]oxazine with hydroxy-, chloro-, and substituted amino groups at the 4-position were synthesized. The structures of the compounds were confirmed by mass-spectrometry and by alternate synthesis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 974–976, July, 1985.     

Molecular modeling and thermoanalytical studies of thermophysical properties of some polymers

The results of computational modeling and experimental data on some thermophysical properties of selected polymers were compared. Different engineering polymers, e.g. polycarbonates and terephthalate polyesters, were considered and their glass transition temperatures and thermal stabilities were determined, by using thermoanalytical methods, e.g. DSC and TG. Measurements were carried out with Perkin-Elmer DSC 7 and TGA 7 instruments. Molecular modeling and computer calculations were performed at the Interdisciplinary Computer Modeling Center (ICM) of Warsaw University, using a Cray El 98 computer and the Insight II software of BIOSYM Technologies Inc. Reasonably good agreement was found between the experimental and calculated values of the glass transition temperatures of the investigated polymers, e.g. for poly(butylene terephthalate)T _g (calc.)=74C andT _g (experim.)=70C. Discrepancies were observed for the temperature of half decompositionT _d,1/2, some of them can be explained by effects of polymer molecular weight and/or char-forming effects.Polymer modeling computations were performed at the Interdisciplinary Computer Modeling Center (ICM) of the Warsaw University, where a CRAY EL 98 computer and the software of BIOSYM Technologies, Inc. were used.     

二氢嘧啶并[4,5-d]嘧啶类衍生物作为集落刺激因子-1受体激酶抑制剂的分子对接和定量构效关系研究

集落刺激因子-1受体激酶（CSF-1R）属于Ⅲ型受体酪氨酸激酶家族成员,其在调控单核巨噬细胞系中发挥重要作用。CSF-1R及其配体异常表达与肿瘤发展过程密切相关。因此,CSF-1R信号传导可成为抗肿瘤治疗的有吸引力的靶标。本文用比较分子场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA）研究了54个二氢嘧啶并[4,5-d]嘧啶类CSF-1R激酶抑制剂的三维定量构效关系（3D-QSAR）。基于配体叠合,CoMFA和CoMSIA模型的交叉验证系数（q2）分别为0.725和0.636,拟合验证系数（r2）分别为0.960和0.958,结果表明这两种模型均具有较好的预测能力。所建模型的等势图能直观反映分子不同取代基对活性的影响,其中立体场和疏水场对活性的贡献较大。通过分子对接研究显示,氨基酸残基Cys666、Asp796在配体和受体结合过程中产生作用,分子对接的结合模式与3D-QSAR得到的结果一致。这些信息为进一步优化CSF-1R激酶抑制剂提供了理论基础。     

Synthesis of 1,4-benzodiazepino[4,5-d][1,4]benzoxazepines

The novel 1,4-benzodiazepino[4,5-d][1,4]benzoxazepine ring system has been constructed via preformed benzoxazepine intermediates. Several derivatives have been prepared as potential anxiolytic agents.