Analysis of electronic structures of physostigmine analogs

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抗有机磷酸酯药物的合成及其构效关系的研究

本文报道一类双吡啶季铵盐化合物,对抗小鼠有机磷酸酯化合物中毒有效,其中一些化合物的抗毒效价超过了文献报道的HI-6,HGG-42的水平。为探讨其构效关系,用EHMO方法计算了23个化合物的分子轨道指数,从中发现吡啶环Ⅱ和羰基可能是化合物的活性部位,影响抗毒作用的因素有二个,并再次设计合成了二个新化合物,量化计算预测的抗毒效价与药理结果一致。化合物与胆碱N受体结合有较强的选择性,根据计算,提出了其可能的作用模式,推测N受体活性部位除有文献报道的阴离子部位、亲酯中心、疏水区域外,还可能有轨道作用部位。     

In silico identification of the active conformation of open-chain enaminones with anticonvulsant activity

A study about the relationship between molecular properties of open-chain enaminones and their anticonvulsant activity is presented in this paper. Geometry optimizations of the enaminones were performed at HF and DFT/B3LYP levels of theory using 6-31 + G(d) basis set. The HOMO and LUMO energies were obtained at the same level of theory. The solvent effect was studied through IPCM. A natural bond orbital (NBO) analysis was performed to analyze the possible association between the stability and the intramolecular hydrogen bond interaction energies. The stability order of the isomers in gas phase was the following: cis-1 > trans-4 > cis-2 > trans-3. The IPCM method showed that the trans-3 isomers are more stable that the cis-2 when the solvent effect was taken into account. Two important intramolecular hydrogen bonds were found by NBO analysis. According to our findings, these interactions could affect the activity of the two most stable isomers (cis-1 and trans-4). By contrast, trans-3 isomers did not present this type of interaction. Therefore, the latter isomers have a large flexibility and can adopt a conformation similar to the conformation of active ringed enaminones. In addition, HOMO and LUMO energies suggested that the trans-3 isomers could be the most reactive species.     

The use of atomic charges and orbital energies as hydrogen-bonding-donor parameters for QSAR studies: comparison of MNDO, AM1 and PM3 methods

Hydrogen-bonding, important in drug-receptor interactions, also determines the solubility and partitioning of drugs between phases. It is, therefore, important to incorporate the effects of hydrogen-bonding in studies of quantitative structure-activity relationships (QSAR). In this study the atomic charge on the most positively charged hydrogen atom in a molecule and the energy of the lowest unoccupied molecular orbital (LUMO) have been used as a measure of hydrogen-bond-donor capacity. For several hydrogen-bonding acids the Mulliken atomic charges and the energy of the LUMO produced by use of three semiempirical methods, AM1, PM3 and MNDO, and MNDO electrostatic-potential-derived atomic charges, have been compared in correlations with solvatochromic hydrogen-bonding acidity (sigmaalpha(H)2). Atomic charges and LUMO energies, particularly those calculated by use of the AM1 and MNDO methods, were found to correlate well with sigmaalpha(H)2. They were also found to be good models of hydrogen-bonding in QSAR correlations.     

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Aim:

To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function.

Methods:

Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer''s randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory.

Results:

Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski''s Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE''s active site. To confirm the inhibitors'' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1.

Conclusion:

This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.     

A structure-activity relationship study of the affinity of selected imidazo[1,2-a]pyridine derivatives, congeners of zolpidem, for the omega 1-subtype of the benzodiazepine receptor

A series of 6-substituted 2-aryl-N,N-dimethylimidazol[1,2-a] pyridine-3-acetamides, congeners of zolpidem and alpidem, was synthesized and tested in vitro for binding with the benzodiazepine receptor in the competition with 3H-zolpidem as an omega 1-selective radioligand. Molecular electrostatic potential (MEP) and the HOMO and LUMO energies were calculated for the compounds by semi-empirical quantum chemistry methods. The lipophilicity parameter of the compounds, expressed as the logarithm of the octanol-water partition coefficient (log P), was calculated; alternatively, standard values of the Hansch hydrophobic substituent constants pi were used. In agreement with earlier investigations on the benzodiazepine receptor ligands with a high preference for the omega 1-subtype, a quantitative correlation of the biological data with molecular parameters has revealed a significant dependence (r = 0.954) of the binding affinity (IC50) on the deepest MEP minimum, in this case associated with the amide carbonyl oxygen atom. The lipophilicity parameters were found to be of lower significance.     

Novel selective inhibitors of hydroxyxanthone derivatives for human cyclooxygenase-2

Aim： To screen the selective inhibitors for human cyclooxygenase-2 （（h）COX-2） utilizing molecular simulation. Methods： Eight xanthone derivatives, compounds A-H, were employed by the structure-based research methodology. Resveratrol and NS-398 were selected as the control compounds for COX-1 and COX-2, respectively. The docking results were scored and the interaction energies of the complexes were calculated by CHARMm forcefield. Results： NS-398 could not dock into the active site of COX-1. However, resveratrol, the specific selective compound for COX-1, gained lower interaction energy while docked in COX-1. The lower interaction energies were investigated, while compound B and F were docked into the catalytic sites of COX- 1 and COX-2, respectively. Compound A, 1,3,6,7-tetrahydroxyxanthone, revealed high inhibitory potency to both COX-1 and COX-2. Conclusion： The conformations of the docking would influence the values of interaction energies. The hydrogen bond could also increase the stabi- lity of the whole complex, which might suggest that compound B had a suitable conformation in the tunnel-like active site of COX-1. Compound F, a potent agent for COX-2, revealed a strong hydrogen bond with Ser516 in human COX-2 to form a stable complex.     

Development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). Rational design of novel, selective, and highly potent BuChE inhibitors

Tacrine heterobivalent ligands were designed as novel and reversible inhibitors of cholinesterases. On the basis of the investigation of the active site gorge topology of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) and by using flexible docking procedures, molecular modeling studies formulated the hypothesis of extra interaction sites in the active gorge of hBuChE, namely, a mid-gorge interaction site and a peripheral interaction site. The design strategy led to novel BuChE inhibitors, balancing potency and selectivity. Among the compounds identified, the heterobivalent ligand 4m, containing an amide nitrogen and a sulfur atom at the 8-membered tether level, is one of the most potent and selective BuChE inhibitors described to date. The novel inhibitors, bearing postulated key features, validated the hypothesis of the presence of extra interaction sites within the hBuChE active site gorge.