Cell inhibition, QSAR

In another study concerning the conformational requirements of I-cyclopropyl-quinolones and their relationship to DNA gyrase inhibition, the conformation-ally constrained cyclopropane derivative (62), related to ofloxacin was prepared and evaluated in whole cells and for inhibition of DNA gyrase [95] the gem-dimethyl analogue (35), discussed earlier in the context of QSAR studies... 

Wang, D.F., Wiest, O., Helquist, P., Lan-Hargest, H.Y. andWiech, N.L. (2004) QSAR studies of PC-3 cell line inhibition activity of TSA and SAHA-like hydroxamic acids. Bioorganic ei Medicinal Chemistry Letters, 14, 707-711. 

The most recent example of in silico efflux modeling has been based on Caco-2 permeability measured in the basal to apical direction [100]. This model can be very effective at ruling out compounds that most likely will show low in vivo intestinal absorption - however it carmot indicate which efflux pump(s) is/are responsible for that, making it more difficult for designers to circumvent the problem. Johnson [92] also included in his review an excellent summary of QSAR models and rules of thumb developed for P-gp substrates and inhibitors. These models are normally based on efflux ratios from MDCK/MDRl or Caco-2 cell lines - in the latter case it is important to notice that the data is combined with inhibition values from the calcein-AM assay, as the observed efflux might not be exclusively due to P-gp. 

A more recent analysis of 104 compounds tested in either CHO cells or human embryonic kidney (HEK) cells for inhibition of the hERG K channel was carried out by Yoshida and Niwa. They obtained the following QSAR ... 

Accordingly it appears that further QSAR investigations should focus separately on those parameters facilitating both cell wall penetration and those required for DNA gyrase inhibition. Then it should be possible to design structures which would maximize both responses. 

Dihydrofolate reductase (DHFR) is by far the most extensively investigated enzyme. 3D structures of binary and ternary DHFR complexes from different bacteria and vertebrates have been published and an extremely large numter of QSAR equations have been derived, both for the isolated enzyme and for growth inhibition of whole cells [288, 396, 431, 432, 671, 677 — 691]. Due to the central role of DHFR in purine biosynthesis, DHFR inhibitors are therapeutically important as highly selective antibacterial (trimethoprim), antimalarial, and antitumor agents (methotrexate). 

Much work has been done to elucidate the molecular mechanisms of drug resistance [756]. Comparative QSAR equations were derived for the inhibition of bacterial DHFR, bacterial cell cultures [213, 214, 288, 432, 677, 685], and different tumor cell lines [288, 432, 671, 678, 679, 681, 684, 687], all being sensitive and resistant to methotrexate (MTX), e.g. eqs. 156—161. 

Other work described the synthesis, 3D QSAR(quantitative structure-activity relationship) investigation, molecular modeling, and various biological evaluations of new 5-indolylthienotriazine 5, produced by a well-known procedure of cyclization with sodium nitrite in hydrochloric acid starting from 3-aminothiophene 6. The product exhibited an inhibition of KDR (kinase domain receptor) activity and human umbilical vein endothelial cell (HUVEC) proliferation (13EJMC765). 

NRI] assay, Coomassie blue [CB] assay, and cellular growth rate [CGR] assay) to develop QSARs to predict IC50 values, that is, the concentration that inhibited 50% of the L-929 cell line of murine fibroblasts (Table 5.20). In addition, Sauvant et al. (1997) developed a QSAR to predict the IC50 values for the ciliated protozoa, Tetrahymena pyriformis GL, using the doubling time from a T. pyriformis GL population assay or DTP (Table 5.20). 

In these models, Ki is the enzyme inhibition constant and IC90 is the concentration of inhibitor resulting in 90% inhibition of viral RNA production in HIV-infected MT-2 cells. The presence of bilinear hydrophobic terms in QSAR 2 3, where there are ahphatic variations at the P2/P2 position of 16 indicate that hydrophobic interactions are important up to a rather high value Ki 6.53, IC90 6.96). Steric interaction of the X-substituent was also found to... 

QSAR 48 was derived [ 14] for the antiviral data of hydroxyethylene isostere derivatives (40) for inhibition of HIV protease in H9 human T-lymphocytes cells, reported by De Solms et al. [160]. One of the prototype pentapeptides (L-682,679) was modified at the carboxy terminus and mostly variations of the P2 amino acid and the elimination/replacement of the P3 amino acid were studied [160]. This model showed that overall bulky molecules would favor the activity. However, the X-substituents would have a negative steric effect. 

IC50 and Ki data of the hydroxyethyl sulfonamide isostere (46) measured for the inhibition of recombinant HIV protease in GEM cells by Vazquez et al. [175] was modeled as QSAR 55 and 56 [14]. A sulfonamido moiety in place of the Pi/Pi amide linkage was studied in this series for the first time. These models showed that the width of the X-substituent is important for activity. The authors [14] mentioned that no effect of Y-substituent was ob-... 

R. G. Booth, C. D. Selassie, C. Hansch, and D. V. Santi,. Med. Chem., 30, 1218 (1987). QSAR of Triazine-antifolate Inhibition of Leishmania DHFR and Cell Growth. 

QSAR data on substituted 2-phenylpyridazinones have shown that the electronic properties of substituents strongly influence activity but can be countered by lipophilicity. Data from whole cells and cell extracts of Aphanocapsa correlated well, with the in vitro results showing a linear relationship between lipophilicity and inhibition of phytoene desaturase in accordance with the QSAR equation for intact cells. ... 

This way the presented variational QSAR anti-HIV mechanism assures the stabilization of pyrimidine complex with the enzyme transcriptase receptor towards the concerned apoptosis of the HIV cells through inhibiting his enzymic activities for further actions (and replications) in organism. 

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