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1.
Aleem Gangjee Xin Lin Lisa R. Biondo Sherry F. Queener 《Bioorganic & medicinal chemistry》2010,18(4):1684-1701
We report the development of CoMFA analysis models that correlate the 3D chemical structures of 80 compounds with 6–5 fused ring system synthesized in our laboratory and their inhibitory potencies against tgDHFR and rlDHFR. In addition to conventional CoMFA analysis, we used two routines available in the literature aimed at the optimization of CoMFA: all-orientation search (AOS) and cross-validated r2-guided region selection (q2-GRS) to further optimize the models. During this process, we identified a problem associated with q2-GRS routine and modified using two strategies. Thus, for the inhibitory activity against each enzyme (tgDHFR and rlDHFR), five CoMFA models were developed using the conventional CoMFA, AOS optimized CoMFA, the original q2-GRS optimized CoMFA and the modified q2-GRS optimized CoMFA using the first and the second strategy. In this study, we demonstrate that the modified q2-GRS routines are superior to the original routine. On the basis of the steric contour maps of the models, we designed four new compounds in the 2,4-diamino-5-methyl-6-phenylsulfanyl-substituted pyrrolo[2,3-d]pyrimidine series. As predicted, the new compounds were potent and selective inhibitors of tgDHFR. One of them, 2,4-diamino-5-methyl-6-(2′,6′-dimethylphenylthio)pyrrolo[2,3-d]pyrimidine, is the first 6–5 fused ring system compound with nanomolar tgDHFR inhibitory activity. The HCl salt of this compound was also prepared to increase solubility. Both forms of the drug were tested in vivo in a Toxoplasma gondii infection mouse model. The results indicate that both forms were active with the HCl salt significantly more potent than the free base. 相似文献
2.
Abstract Two RNA sequences, AAA and AUG, were studied by the conformational search program CICADA and by molecular dynamics (MD) in the framework of the AMBER force field, and also via thorough PDB database search. CICADA was used to provide detailed information about conformers and conformational interconversions on the energy surfaces of the above molecules. Several conformational families were found for both sequences. Analysis of the results shows differences, especially between the energy of the single families, and also in flexibility and concerted conformational movement. Therefore, several MD trajectories (altogether 16 ns) were run to obtain more details about both the stability of conformers belonging to different conformational families and about the dynamics of the two systems. Results show that the trajectories strongly depend on the starting structure. When the MD start from the global minimum found by CICADA, they provide a stable run, while MD starting from another conformational family generates a trajectory where several different conformational families are visited. The results obtained by theoretical methods are compared with the thorough database search data. It is concluded that all except for the highest energy conformational families found in theoretical result also appear in experimental data. Registry numbers: adenylyl-(3′ →5′)-adenylyl-(3′ →5′)-adenosine [917-44-2] adenylyl-(3′ →5′)-uridylyl-(3′ →5′)-guanosine [3494-35-7] 相似文献
3.
Abstract Taboo-based Monte Carlo search which restricts the sampling of the region near an old configuration, is developed. In this procedure, Monte Carlo simulation and random search method are combined to improve the sampling efficiency. The feasibility of this method is tested on global optimization of a continuous model function, melting of the 256 Lennard-Jones particles at T? = 0.680 and ρ? = 0.850 and polypeptides (alanine dipeptide and Metenkephalin). From the comparison of results for the model function between our method and other methods, we find the increase of convergence rate and the high possibility of escaping from the local energy minima. The results of the Lennard-Jones solids and polypeptides show that the convergence property to reach the equilibrium state is better than that of others. It is also found that no significant bias in ensemble distribution is detected, though taboo-based Monte Carlo search does not sample the correct ensemble distribution owing to the restriction of the sampling of the region near an old configuration. 相似文献
4.
Yuanqiang Wang Heng Zhang Yong Lin Qi Zhao Hui Liu Zhan Zhang Qingyou Xia Bo Zhu Zhihua Lin 《Journal of molecular modeling》2011,17(1):1-8
Phenols and its analogues are known to induce caspase-mediated apoptosis activity and cytotoxicity on various cancer cell
lines. In the current work, two types of molecular field analysis techniques were used to perform the three dimension quantitative
structure activity relationship (3D-QSAR) modeling between structural characters and anticancer activity of two sets of phenolic
compounds, which are comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).
Then two 3D-QSAR models for two sets of phenolic analogues were obtained with good results. The first QSAR model, which was
derived from CoMFA for phenols with caspase-mediated apoptosis activity against L1210 cells, had good predictability (q
2 = 0.874, r
2 = 0.930), and the other one was derived from CoMSIA for electron-attracting phenols with cytotoxicity in L1210 cell (q
2 = 0.836, r
2 = 0.950). In addition, the CoMFA and CoMSIA contour maps provide valuable guidance for designing highly active phenolic compounds. 相似文献
5.
Priyanka Shah Sumit Kumar Sunita Tiwari Mohammad Imran Siddiqi 《Journal of chemical biology》2012,5(3):91-103
A series of 35 triazolopyrimidine analogues reported as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors were optimized using quantum mechanics methods, and their binding conformations were studied by docking
and 3D quantitative structure–activity relationship studies. Genetic algorithm-based criteria was adopted for selection of
training and test sets while maintaining structural diversity of training and test sets, which is also very crucial for model
development and validation. Both the comparative molecular field analyses (
q\textLOO2 = 0.841 q_{\text{LOO}}^2 = 0.{841} ,
r\textncv2 = 0.99 r_{\text{ncv}}^2 = 0.{99} ) and comparative molecular similarity indices analyses (
q\textLOO2 = 0.757 q_{\text{LOO}}^2 = 0.{757} ,
r\textncv2 = 0.943 r_{\text{ncv}}^2 = 0.{943} ) show excellent correlation and high predictive power. Furthermore, molecular dynamics simulations were performed to explore
the binding mode of the two of the most active compounds of the series, 10 and 14. Harmonization in the two simulation results validate the analysis and therefore applicability of docking parameters based
on crystallographic conformation of compound 14 bound to receptor molecule. This work provides useful information about the inhibition mechanism of this class of molecules
and will assist in the design of more potent inhibitors of PfDHODH. 相似文献
6.
7.
Solvent-induced electrostatic potentials and field components at thesolute sites of model Na+q–Cs-q molecules were computed bysumming over either solvent charges (q-summation) or solventmolecular centers (M-summation) from molecular dynamics simulations.These were compared with values obtained by solving Poisson equation withthe dielectric boundary defined by R
eff = (R
atom
+R
gmax )/2.q-summation using cut-offs that are 10 Å generallyunderestimates or overestimates the magnitude of (a) the potentials and field components atNa+q and Cs-q relative to the theoretical values and (b)electrostatic solvation free energies of the dipolar solutes assuminglinear solvent response relative to the respective values from free energysimulations. Furthermore, the q-summed electric potentials showedsignificant oscillations even beyond the second hydration shell. Incontrast, the corresponding M-summed potentials plateaued after thefirst hydration shell. Although the different water molecular centersyielded different converged potential values, the dipole center producedvalues in remarkable agreement with the theoretical values for solutecharges ranging from 1 to 0.1e, indicating the existence of an a convenient molecular center for computing these quantities. In contrast to theM-summed potentials, the electrostatic field components andelectrostatic solvation free energies from linear response relationshipswere found not to be sensitive to the choice of the molecular centerfor typical cut-off distances (8 to 12 Å) used in most simulations. 相似文献
8.
9.
We developed a search algorithm combining Monte Carlo (MC) and self-consistent mean field techniques to evolve a peptide sequence that has good binding capability to the anticodon stem and loop (ASL) of human lysine tRNA species, tRNALys3, with the ultimate purpose of breaking the replication cycle of human immunodeficiency virus-1. The starting point is the 15-amino-acid sequence, RVTHHAFLGAHRTVG, found experimentally by Agris and co-workers to bind selectively to hypermodified tRNALys3. The peptide backbone conformation is determined via atomistic simulation of the peptide-ASLLys3 complex and then held fixed throughout the search. The proportion of amino acids of various types (hydrophobic, polar, charged, etc.) is varied to mimic different peptide hydration properties. Three different sets of hydration properties were examined in the search algorithm to see how this affects evolution to the best-binding peptide sequences. Certain amino acids are commonly found at fixed sites for all three hydration states, some necessary for binding affinity and some necessary for binding specificity. Analysis of the binding structure and the various contributions to the binding energy shows that: 1) two hydrophilic residues (asparagine at site 11 and the cysteine at site 12) “recognize” the ASLLys3 due to the VDW energy, and thereby contribute to its binding specificity and 2) the positively charged arginines at sites 4 and 13 preferentially attract the negatively charged sugar rings and the phosphate linkages, and thereby contribute to the binding affinity. 相似文献
10.
Saswati Chatterjee-Das Erik P. Lillehoj Diana M. Hernandez John E. Coligan David H. Sachs 《Immunogenetics》1987,25(1):7-14
To analyze how many D-region-encoded molecules could be detected inH-2
q
, we produced a panel of nine monoclonal antibodies from AKR (KkDk) anti-AKR.M (KkDq) immunizations. All of the Dq region antibodies cross-reacted on Dd and/or Ld, and all except one cross-reacted on Db, confirming the previously observed serologic and amino acid sequence homology between theD-region products ofH-2
d
,H-2
b
, andH-2
q
. All of these monoclonal antibodies precipitated 46 000 dalton molecules from both cell-surface-labeled and biosynthetically labeled BIO.AKM spleen cells, indicating that all were reactive with class I-like molecules. Sequential immunoprecipitation analysis with one of these antibodies, 66-3-5, reveals the presence of a previously unidentified class I-like molecule. Tryptic peptide map analysis reveals that this molecule may be the product of a newly describedH-2D
q
-region gene. 相似文献
11.
Yuanjian Guo Lu Yang Katrina Haught Suzanne Scarlata 《The Journal of biological chemistry》2015,290(27):16698-16707
Caveolae are membrane invaginations that can sequester various signaling proteins. Caveolae have been shown to provide mechanical strength to cells by flattening to accommodate increased volume when cells are subjected to hypo-osmotic stress. We have previously found that caveolin, the main structural component of caveolae, specifically binds Gαq and stabilizes its activation state resulting in an enhanced Ca2+ signal upon activation. Here, we show that osmotic stress caused by decreasing the osmolarity in half reversibly changes the configuration of caveolae without releasing a significant portion of caveolin molecules. This change in configuration due to flattening leads to a loss in Cav1-Gαq association. This loss in Gαq/Cav1 association due to osmotic stress results in a significant reduction of Gαq/phospholipase Cβ-mediated Ca2+ signals. This reduced Ca2+ response is also seen when caveolae are reduced by treatment with siRNA(Cav1) or by dissolving them by methyl-β-cyclodextran. No change in Ca2+ release with osmotic swelling can be seen when growth factor pathways are activated. Taken together, these results connect the mechanical deformation of caveolae to Gαq-mediated Ca2+ signals. 相似文献
12.
3D-QSAR studies on the derivatives of 1-(3,3-diphenylpropyl)-piperidinyl amide and urea as CCR5 receptor antagonists were
performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to
rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy
conformer of the template molecule, the most active and pharmacokinetically stable molecule of the series, was obtained by
systematic search and used to build structures of the molecules in the dataset. The best predictions for the CCR5-receptor
were obtained with the CoMFA standard model (q
2 = 0.787, r
2 = 0.962) and CoMSIA model combined steric, electrostatic and hydrophobic fields (q
2 = 0.809, r
2 = 0.951). The predictive ability of CoMFA and CoMSIA were determined using a test set of 12 compounds giving predictive correlation
coefficients of 0.855 and 0.83, respectively, indicating good predictive power. Further, the robustness of the model was verified
by bootstrapping analysis. The contour maps produced by the CoMFA and CoMSIA models were used to identify the structural features
relevant to the biological activity in this series. Based on the CoMFA and CoMSIA analysis, we have identified some key features
in the series that are responsible for CCR5 antagonistic activity which may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl
derivatives and predict their activity prior to synthesis.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
13.
Peter B Boucher Ian Paynter David A Orwig Ilan Valencius Crystal Schaaf 《Annals of botany》2021,128(6):689
Background and AimsTerrestrial laser scanners (TLSs) have successfully captured various properties of individual trees and have potential to further increase the quality and efficiency of forest surveys. However, TLSs are limited to line of sight observations, and forests are complex structural environments that can occlude TLS beams and thereby cause incomplete TLS samples. We evaluate the prevalence and sources of occlusion that limit line of sight to forest stems for TLS scans, assess the impacts of TLS sample incompleteness, and evaluate sampling strategies and data analysis techniques aimed at improving sample quality and representativeness.MethodsWe use a large number of TLS scans (761), taken across a 255 650-m2 area of forest with detailed field survey data: the Harvard Forest Global Earth Observatory (ForestGEO) (MA, USA). Sets of TLS returns are matched to stem positions in the field surveys to derive TLS-observed stem sets, which are compared with two additional stem sets derived solely from the field survey data: a set of stems within a fixed range from the TLS and a set of stems based on 2-D modelling of line of sight. Stem counts and densities are compared between the stem sets, and four alternative derivations of area to correct stem densities for the effects of occlusion are evaluated. Representation of diameter at breast height and species, drawn from the field survey data, are also compared between the stem sets.Key ResultsOcclusion from non-stem sources was the major influence on TLS line of sight. Transect and point TLS samples demonstrated better representativeness of some stem properties than did plots. Deriving sampled area from TLS scans improved estimates of stem density.ConclusionsTLS sampling efforts should consider alternative sampling strategies and move towards in-progress assessment of sample quality and dynamic adaptation of sampling. 相似文献
14.
Lina Ding Zhi-Zheng Wang Xu-Dong Sun Jing Yang Chao-Ya Ma Wen Li Hong-Min Liu 《Bioorganic & medicinal chemistry letters》2017,27(15):3521-3528
Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q2 = 0.802, r2ncv = 0.979, and the best CoMSIA model has q2 = 0.799, r2ncv = 0.982. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300 K. All the results can provide us more useful information for our further drug design. 相似文献
15.
Atomic resolution and coarse-grained simulations of dimyristoylphosphatidylcholine lipid bilayers were analyzed for fluctuations perpendicular to the bilayer using a completely Fourier-based method. We find that the fluctuation spectrum of motions perpendicular to the bilayer can be decomposed into just two parts: 1), a pure undulation spectrum proportional to q−4 that dominates in the small-q regime; and 2), a molecular density structure factor contribution that dominates in the large-q regime. There is no need for a term proportional to q−2 that has been postulated for protrusion fluctuations and that appeared to have been necessary to fit the spectrum for intermediate q. We suggest that earlier reports of such a term were due to the artifact of binning and smoothing in real space before obtaining the Fourier spectrum. The observability of an intermediate protrusion regime from the fluctuation spectrum is discussed based on measured and calculated material constants. 相似文献
16.
Cell-mediated lymphocytotoxicity was generated in four strain combinations differing only by the cell-surface expression of the class II E molecule controlled by the H-2 complex. The four combinations were: B10.D2(R107) anti-B10.A(3R), B10.A(4R) anti-B10.A(2R), B10.GD anti-B10.D2(R101), and B10.S(7R) anti-B10.S(9R). In all four of these combinations, the stimulator expresses E molecules on the cell surface, while the responder does not. The cytolytic T lymphocytes generated in the B10.D2(R107) anti-B10.A(3R) and B10.A(4R) anti-B10.A(2R) combinations reacted not only with the stimulator but also with strains that do not express cell-surface E molecules, in particular, strains carrying the H-2
f
and H-2
q
haplotypes. The cross-reactivity with E-negative strains could be blocked by monoclonal antibodies specific for the Af or Aq molecules but not by antibodies recognizing determinants on E or class I (K) molecules. The anti-H-2f cross-reactivity could be inhibited by H-2
q
cold targets and, reciprocally, the anti-H-2q reactivity could be blocked by H-2
f
cold targets. These findings are interpreted as indicating that the cytolytic T lymphocytes stimulated by E molecules can recognize and lyse cells lacking E molecules but expressing A molecules. The observed E-A cross-reactivity supports the notion of structural and functional relatedness between the A and E molecules and suggests a common evolutionary origin of the A- and E-encoding loci. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(2):667-673
Three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety were performed to understand the mechanism of action and structure–activity relationship of these compounds. Contour map analysis indicated that steric contributions of the adamantyl moiety and electrostatic contributions of the hydroxyl group at the 3-position are important in the activity. Activities of the training set and test sets predicted by CoMFA fit well with actual activities, demonstrating that CoMFA, along with the best calculated q2 value, has the best predictive ability. 相似文献
18.
19.
Diabetes remains a life-threatening disease. The clinical profile of diabetic subjects is often worsened by the presence of
several long-term complications, for example neuropathy, nephropathy, retinopathy, and cataract. Comparative molecular field
analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 2,4-thiazolidinediones
derivatives as aldose reductase (ALR2) inhibitors. Molecular ligand superimposition on a template structure was finished by
the database alignment method. The 3D-QSAR models resulted from 44 molecules gave q
2 values of 0.773 and 0.817, r
2 values of 0.981 and 0.979 for CoMFA and CoMSIA, respectively. The contour maps from the models indicated that a large volume
group next to the R-substituent will increase the ALR2 inhibitory activity. In fact, adding a -CH2COOH substituent at the R-position would generate a new compound with higher predicted activity. 相似文献