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101.
102.
《Expert opinion on drug discovery》2013,8(6):543-557
Importance of the field: CC-chemokine receptor 2 (CCR2) belongs to the GPCR superfamily and is the primary receptor for monocyte chemoattractant protein-1 (MCP-1), also known as chemokine ligand CCL2. Studies indicate the possible involvement of MCP-1 and CCR2 in various disease conditions, such as rheumatic arthritis, multiple sclerosis, vascular diseases, obesity and diabetes, via the inflammatory pathway. MCP-1 and CCR2 knockout mice under a broad range of stimuli exhibit deficient monocyte recruitment suggesting its potential role in inflammation. Overall, there is evidence that an impairment of monocyte trafficking in inflammation models occurs when there is a loss of MCP-1 effector function. This makes its receptor, CCR2, an attractive target for pharmaceutical research. Several small molecular CCR2 antagonists have been developed, particularly in the industry.Areas covered in this review: In this article, we have summarized the in silico work carried out in the area of CCR2 and reviewed mainly the computer aided drug design (CADD) studies reported on quantitative structure–activity relationship, homology modeling, molecular docking and virtual screening.What the reader will gain: A survey of computational studies for the rational design and development of CCR2 antagonists.Take home message: CADD tools can be used to rationalize the identification of the potential leads and these techniques can be effectively applied in the rapid searching of novel and potent CCR2 antagonists. 相似文献
103.
《Expert opinion on drug discovery》2013,8(2):133-153
Introduction: Molecular topology (MT) has emerged in recent years as a powerful approach for the in silico generation of new drugs. One key part of MT is that, in the process of drug design/discovery, there is no need for an explicit knowledge of a drug's mechanism of action unlike other drug discovery methods. Areas covered: In this review, the authors introduce the topic by explaining briefly the most common methodology used today in drug design/discovery and address the most important concepts of MT and the methodology followed (QSAR equations, LDA, etc.). Furthermore, the significant results achieved, from this approach, are outlined and discussed. Expert opinion: The results outlined herein can be explained by considering that MT represents a new paradigm in the field of drug design. This means that it is not only an alternative method to the conventional methods, but it is also independent, that is, it represents a pathway to connect directly molecular structure with the experimental properties of the compounds (particularly drugs). Moreover, the process can be realized also in the reverse pathway, that is, designing new molecules from their topological pattern, what opens almost limitless expectations in new drugs development, given that the virtual universe of molecules is much greater than that of the existing ones. 相似文献
104.
P. Bhatia M. Kolinski R. Moaddel K. Jozwiak I. W. Wainer 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(7-8):656-675
1.?Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule–drug transporter binding.2.?This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies.3.?The use of stereochemical data in quantitative structure–activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule–drug transporter interactions take place in three-dimensional and asymmetric space. 相似文献
105.
106.
Najim A. Al‐Masoudi Bayazeed H. Abdullah Ali H. Essa Roberta Loddo Paolo LaColla 《Archiv der Pharmazie》2010,343(4):222-227
The palladium complexes [(dppe)Pd(L)2PdCl2], [(dppe)Pd(L)2PtCl2], [(dppp)Pd(L)2PdCl2], [(dppm) Pd(L)2NiCl2], and [(dppm)Pd(L)2SnCl4] 15–19 were prepared. The antiproliferative activity of the newly synthesized complexes as well as their previously prepared analogues 3–14 and 20–26 were screened against a large panel of human cancer cell lines derived from haematological CD4+ human T‐cells containing an integrated HTLV‐1 genome (MT‐4). The complex 12a , b exhibited remarkable antiproliferative activity against MT‐4, CD4+ human acute T‐lymphoblastic leukemia (CCRF‐CEM), human splenic B‐lymphoblastoid cells (WIL‐2NS), human acute B‐lymphoblastic leukemia (CCRF‐SB), skin melanoma (SK‐MEL‐28), and prostate carcinoma (DU145) cell lines (CC50 = 0.5 μM, 0.4 ± 0.05 μM, 0.6 ± 0.05 μM, 0.4 ± 0.1 μM, and 0.8 ± 0.2 μM, respectively), meanwhile, 9a , b , 14a , b , and 23 showed significant activity against the CCRF‐SB cell lines (CC50 = 0.6 ± 0.06 μM, 0.7 ± 0.05 μM, 0.6 ± 0.05 μM, and 0.8 ± 0.15 μM, respectively). Further, 19 exhibited activity against the CCRF‐CEM cell line (CC50 = 0.4 ± 0.05 μM). 相似文献
107.
Although herbal medicinal products (HMP) have been perceived by the public as relatively low risk, there has been more recognition of the potential risks associated with this type of product as the use of HMPs increases. Potential harm can occur via inherent toxicity of herbs, as well as from contamination, adulteration, plant misidentification, and interactions with other herbal products or pharmaceutical drugs. Regulatory safety assessment for HMPs relies on both the assessment of cases of adverse reactions and the review of published toxicity information. However, the conduct of such an integrated investigation has many challenges in terms of the quantity and quality of information. Adverse reactions are under-reported, product quality may be less than ideal, herbs have a complex composition and there is lack of information on the toxicity of medicinal herbs or their constituents. Nevertheless, opportunities exist to capitalise on newer information to increase the current body of scientific evidence. Novel sources of information are reviewed, such as the use of poison control data to augment adverse reaction information from national pharmacovigilance databases, and the use of more recent toxicological assessment techniques such as predictive toxicology and omics. The integration of all available information can reduce the uncertainty in decision making with respect to herbal medicinal products. The example of Aristolochia and aristolochic acids is used to highlight the challenges related to safety assessment, and the opportunities that exist to more accurately elucidate the toxicity of herbal medicines. 相似文献
108.
OBJECTIVE: A large number of structurally and functionally diverse compounds act as substrates or modulators of p-glycoprotein (p-gp). Some of them possess multiple drug resistance (MDR)-reversing activity, but only a small number of them have entered clinical study. In order to uncover the factors which exert a significant impact on the interaction between substrates/modulators and p-gp, we have performed structure-activity relationship (SAR) analyses, including molecular modelling, two-dimensional (2D) and three-dimensional (3D) parameter-frame-setting analysis, quantitative structure activity relationship (QSAR) analysis among substrates/modulators, as well as clinically promising MDR-reversing agents. METHODS: The physicochemical parameters C log P, CMR and all regression equations were derived by using C log P version 4.0 and the latest CQSAR software, respectively. Molecular modelling and all other parameter calculations were performed by using HyperChem version 5.0 program, after geometry optimization and energy minimization using the AM1 semiempirical method. RESULTS: SAR analyses indicate that MDR reversal activity is correlated with the lipophilicity (C log P), molecular weight (log Mw), longest chain (Nlc) of the molecule and the energy of the highest occupied orbital (Ehomo). In addition, the presence of a basic tertiary nitrogen atom in the structure is also an important contributor to p-gp inhibitory activity. Some separation in space is achieved for different subsets of p-gp substrates and inhibitors using Nlc, C log P and Ehomo as three independent parameters in the 3D-parameter-frame setting. CONCLUSION: A highly effective p-gp modulator candidate should possess a log P value of 2.92 or higher, 18-atom-long or longer molecular axis, and a high Ehomo value, as well as at least one tertiary basic nitrogen atom. The results obtained may be useful in explaining drug-p-gp interactions for different compounds, including drug interactions and the development of new MDR chemosensitizers. 相似文献
109.
A rather small data matrix of seven chemicals and 17 different ecotoxicological end points is examined by methods of Discrete Mathematics. Especially, the lattice theory and its variant, the Formal Concept Analysis may be an attractive tool to analyze Quantitative Structure Activity Relationships, when a numerical functional approach is not at hand. The central item is the so called concept, which is a pair of subsets: A subset of molecules and a subset of properties which correspond to each other. The concepts are partially ordered due to a subset relation. From this subset relation, if–then-rules are derived, which aim to relate the structure of molecules with their ecotoxicological properties. For example, the following chemical rule is found: Cl (2A,2C,2M). That means, all substances considered here having a –Cl as structural code have a medium ecotoxicological effect on Daphnia magna , Orconectes immunisare (Crustacea) and on Photobacterium phosphoreum , at least within the training set. 相似文献
110.
Morisseau C Goodrow MH Newman JW Wheelock CE Dowdy DL Hammock BD 《Biochemical pharmacology》2002,63(9):1599-1608
The soluble epoxide hydrolase (sEH) is involved in the metabolism of arachidonic, linoleic, and other fatty acid epoxides, endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas, carbamates, and amides are new potent and stable inhibitors of sEH. However, the poor solubility of the lead compounds limits their use. Inhibitor structure-activity relationships were investigated to better define the structural requirements for inhibition and to identify points in the molecular topography that could accept polar groups without diminishing inhibition potency. Results indicate that lipophilicity is an important factor controlling inhibitor potency. Polar groups could be incorporated into one of the alkyl groups without loss of activity if they were placed at a sufficient distance from the urea function. The resulting compounds had a 2-fold higher water solubility. These findings will facilitate the rational design and optimization of sEH inhibitors with better physical properties. 相似文献