Drug Design and Discovery (Drug Des Discov)

Publisher: Informa Healthcare

Journal description

Drug Design and Discovery is an international journal which publishes original work in aspects of drug design and discovery. The primary focus is on research which addresses the generation and optimization of new lead compounds through rational approaches such as structure-based drug design, molecular modelling, mechanism-based design, or application of structure-activity analysis. Papers which describe novel screening strategies or searching techniques for the discovery and optimisation of novel agents are also published. Research into novel, molecular approaches to the optimisation of drug delivery, pharmacokinetics, or modification of properties through manipulation of metabolism could be considered. The journal will publish full length research papers, short communications and reviews.

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Website Drug Design and Discovery website
Other titles Drug design and discovery (Online), Drug design and discovery
ISSN 1055-9612
OCLC 51540689
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Informa Healthcare

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • On author's personal website or institution website
    • Publisher copyright and source must be acknowledged
    • Non-commercial
    • Must link to publisher version
    • Publisher's version/PDF cannot be used
    • NIH funded authors may post articles to PubMed Central for release 12 months after publication
    • Wellcome Trust authors may deposit in Europe PMC after 6 months
  • Classification

Publications in this journal

  • Source
    Dan Hu ·
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    ABSTRACT: Background: Major depression is diagnosed in 18% of patients following myocardial infarction (MI), and the antidepressant fluoxetine is shown to effectively decrease depressive symptoms and improve coronary heart disease prognosis. We observed the effect of fluoxetine on cardiac electrophysiology in vivo in a rat model of post-MI depression and the potential mechanism. Methods and results: Eighty adult male Sprague Dawley rats (200–250 g) were randomly assigned to five groups: normal control (control group), MI (MI group), depression (depression group), post-MI depression (model group), and post-MI depression treated with intragastric administration of 10 mg/kg fluoxetine (fluoxetine group). MI was induced by left anterior descending coronary artery ligation. Depression was developed by 4-week chronic mild stress (CMS). Behavior measurement was done before and during the experiment. Electrophysiology study in vivo and Western blot analysis were carried on after 4 weeks of CMS. After 4 weeks of CMS, depression-like behaviors were observed in the MI, depression, and model groups, and chronic fluoxetine administration could significantly improve those behaviors (P<0.05 vs model group). Fluoxetine significantly increased the ventricular fibrillation threshold compared with the model group (20.20±9.32 V vs 14.67±1.85 V, P<0.05). Expression of Kv4.2 was significantly reduced by 29%±12%, 24%±6%, and 41%±15%, respectively, in the MI group, CMS group, and model group, which could be improved by fluoxetine (30%±9%). But fluoxetine showed no improvement on the MI-induced loss of Cx43. Conclusion: The susceptibility to ventricular arrhythmias was increased in depression and post-MI depression rats, and fluoxetine may reduce the incidence of ventricular arrhythmia in post-MI depression rats and thus improve the prognosis. This may be related in part to the upregulation of Kv4.2 by fluoxetine.
    Drug Design and Discovery 02/2015; 10(9):763-772. DOI:10.2147/DDDT.S75863
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    ABSTRACT: Neonicotinoids are the most important class of synthetic insecticides increasingly used in agri- culture and veterinary medicine. Fundamental differences between the nicotinic acetylcholine receptors (nAChRs) of insects and mammals confer remarkable selectivity of the neonicoti- noids at insect nAChR over mammalian nAChR. To identify pharmacophoric requirements of azidopyridinyl neonicotinoids for their efficacy and selectivity towards the insect nAChR over the mammalian one, quantitative structure-activity relationship (QSAR) study was performed using electrotopological state atom (ETS A) indices. This study clearly showed that nitroimines, nitromethylenes, and cyanoimines are more selective to Drosophila nAChR and safe for hu- man being, whereas N-substituted imines have affinity to mammalian receptor. Pharmacophore mapping for both the activities was done.
    Drug Design and Discovery 04/2003; 18(2-3):81-89. DOI:10.1080/10559610290249557
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    ABSTRACT: Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-negative bacteria by inhibiting signal peptidase II in the cytoplasmic membrane. Although only one conformation of 1 was observed for the crystal structure, it was revealed by 1H NMR spectroscopic analysis that 1 exists as a mixture of two rotational isomers in solution (CDCl3 and CD3OD). A conformational analysis of 1 was, therefore, performed by high-temperature molecular dynamics simulation in combination with 1H NMR analysis to elucidate the conformations in solution. The relative ratio of the major and minor isomers present, which differs depending on the solvent, was then derived from their relative energy differences obtained in the conformational analysis. The difference in the relative ratios corresponded with that calculated from the 1H NMR analysis. Finally, the predicted conformations in solution were compared with that of the X-ray crystal structure to find local and global differences that characterize these conformations.
    Drug Design and Discovery 02/2003; 18(4):109-16. DOI:10.1080/10559610390450723
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    ABSTRACT: Relationship between the topological indices and acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) inhibitory activity of (aminosulfonyl)ureas has been investigated. Three topological indices, Wiener's index--a distance-based topological descriptor, molecular connectivity index--an adjacency-based topological index, and eccentric connectivity index--an adjacency-cum-distance-based topological descriptor, were used for the present investigations. A data set comprising 41 analogues of substituted (aminosulfonyl)ureas was selected for the present studies. The values of wiener's index, eccentric connectivity index, and molecular connectivity index for each of the 41 compounds comprising the data set were computed using an in-house computer program. Resultant data were analyzed and suitable models were developed after identification of active ranges. Subsequently, a biological activity was assigned to each compound using these models, which was then compared with the reported in vitro ACAT inhibitory activity. Accuracy of prediction using these models was found to vary from a minimum of approximately 83% to a maximum of approximately 91%.
    Drug Design and Discovery 02/2003; 18(4):117-22. DOI:10.1080/10559610390464124
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    ABSTRACT: Sulfonamide hydroxamate derivatives of anthranilic acids are known to be potent inhibitors of cell-free TACE enzyme. However, compounds of this structural class with both high potency and high selectivity for TACE over matrix metalloproteinases (MMPs) are uncommon. Replacement of the sulfonamide functionality with an isosteric sulfonate ester has resulted in a series of sulfonate ester hydroxamates, 2a-e, with excellent activity against TACE and excellent selectivity over MMP-1 and MMP-13. Although compounds 2a-e possess good permeability in a PAMPA assay, they are only weakly active as inhibitors of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production in human monocytic THP-1 cells. Protein binding affinity also does not predict the lack of cellular activity for these analogs.
    Drug Design and Discovery 02/2003; 18(4):123-6. DOI:10.1080/10559610390476473
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    ABSTRACT: Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.
    Drug Design and Discovery 02/2003; 18(2-3):65-79. DOI:10.1080/10559610290249539
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    ABSTRACT: Neonicotinoids are the most important class of synthetic insecticides increasingly used in agriculture and veterinary medicine. Fundamental differences between the nicotinic acetylcholine receptors (nAChRs) of insects and mammals confer remarkable selectivity of the neonicotinoids at insect nAChR over mammalian nAChR. To identify pharmacophoric requirements of azidopyridinyl neonicotinoids for their efficacy and selectivity towards the insect nAChR over the mammalian one, quantitative structure-activity relationship (QSAR) study was performed using electrotopological state atom (ETSA) indices. This study clearly showed that nitroimines, nitromethylenes, and cyanoimines are more selective to Drosophila nAChR and safe for human being, whereas N-substituted imines have affinity to mammalian receptor. Pharmacophore mapping for both the activities was done.
    Drug Design and Discovery 02/2003; 18(2-3):81-9. DOI:10.3109/10559610290249557
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    ABSTRACT: The methods of bioinformatics, molecular modelling, and quantitative structure-activity relationships (QSARs) using regression and artificial neural network (ANN) analyses were applied to develop safer aldoxime antidotes against poisoning by organophosphorus (OP) agents with high, mean, and low aging rates. We start here from a molecular modelling of the mouse AChE at an atomistic level. Aim is to predict qualitatively the structural requirements of an aldoxime that shows an unique reactivating activity against the three classes of OPs. An antidotal action should occur by a three-site mechanism: the aldoxime groups of the first pyridinium ring should point towards the catalytic site, and the second pyridinium ring and its substituents should be anchored at the peripherical and anionic subsites. Based on this model, it is predicted that a suitable substituent is based on an arginine-like moiety. Then, an ANN-based QSAR analysis using a training set of aldoximes with known structure and activities was applied. Its input layer consisted of seven nodes: the group-membership descriptors that parameterize the type of the OP, the logarithms of the distribution coefficients at pH 7.4 and their squared term, the lowest unoccupied molecular orbital (LUMO) energies, the scaled molar refractions of the substituents, and their squared term. It was shown that the qualitative prediction made by molecular modelling can be quantified by an ANN prediction.
    Drug Design and Discovery 02/2003; 18(4):127-50. DOI:10.1080/10559610390484168
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    ABSTRACT: Strong hydrogen-bonding forces between the Thr26 and Thr26' of the protease stabilize the internal cage of the dimeric triad of the aspartyl HIV-1 protease (Asp25Thr26Gly27 and Asp25' Thr26'Gly27', respectively). The interaction of reversible inhibitors of HIV-1 protease is based on (i) strong hydrogen-bonding forces between the main chain (--CONH--) oxygen atoms of Gly27 and/or Gly27' and hydrogen-bond donating moieties of a drug, and (ii) hydrogen bonds between the oxygen of the catalytic Asp25 and/or Asp25' carboxylates and aliphatic hydroxyl groups of a drug. The free entry of natural substrates into the active-site cavity is sterically hindered by inhibitors, so that the catalytic Asp carboxylates cannot interact with natural substrates. Irreversible inhibitors interact with the nucleophilic carboxylate moiety of Asp25 of HIV-1 protease by covalent bonding.
    Drug Design and Discovery 02/2003; 18(2-3):53-64. DOI:10.1080/10559610290252832
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    ABSTRACT: Thromboxane A(2) receptor antagonists have attracted much attention in recent times in the design of new agents that could be active against diseases such as thrombosis, asthma and myocardial ischemia. 3D-QSAR studies have been performed on a series of [[1-aryl(or benzyl)-1-(benzenesulphonamido)methyl] phenyl] alkanoic acid derivatives by using the receptor surface analysis (RSA) method. The RSA analysis was carried out on 31 analogues of which 25 were used in the training set and the rest considered for the test set. This study produced reasonably good predictive models with good cross-validated and conventional r(2) values in both the models.
    Drug Design and Discovery 02/2003; 18(2-3):47-51. DOI:10.1080/10559610290252869
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    ABSTRACT: Three series of anti-HIV data (reverse transcriptase inhibitory activity, cytopathicity data, and cytotoxicity data) of alkenyldiarylmethanes were modeled with physicochemical, topological and structural descriptors by multiple regression analysis using principal component factor analysis as the data pre-processing step. Molar refractivity was found to be a significant contributor in modeling all three data sets. Apart from this, partition coefficient, E-state index, valence connectivity and indicator parameters were important in modeling different activity series. The final relations were of moderate to good quality as evidenced from regression statistics (R2 values ranging 66-75%) and leave-one-out cross validation data (Q2 values ranging 54-70%).
    Drug Design and Discovery 02/2003; 18(4):165-80. DOI:10.1080/10559610390484221
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    ABSTRACT: Imidazole and oxazole derivatives 1 to 4 were designed and prepared as dipeptide mimetics to replace the Ser-Leu dipeptide sequence of Ro-25-9980 (Ac-(Cha)-RAMA-S-L-NH2), a peptidic inhibitor of antigen binding to major histocompatibility complex (MHC) class II DR molecules linked to rheumatoid arthritis (RA). The most potent analog in binding assays (IC50 = 30 nM in DRB1*0401 binding; 1.6 times as potent as Ro 25-9980) was 16, Ac-(Cha)RAMA-(S)S-psi(oxazole)-L-NH2. The SAR of peptide hybrids 10 to 24, prepared by incorporating the dipeptide mimetics 1 to 4 is discussed. Of these hybrids, 23 and 24, analogs that incorporated the imidazole and oxazole mimetics as well as optimized variants at positions 3 to 5, were found to have 70 to 80 nM binding affinity comparable to the parent peptide in DRB 1*0401 binding and were also active in DRB1*0101 binding, while being resistant to proteolysis by cathepsin B. Both of these compounds showed inhibitory activity in an antigen-stimulated T-cell proliferation assay, indicating their potential to suppress autoimmune responses and as leads for therapeutic agents to treat RA.
    Drug Design and Discovery 02/2002; 18(1):3-7. DOI:10.1080/10559610213501
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    ABSTRACT: Quantitative structure-activity relationship (QSAR) study of human factor Xa inhibitor N2-aroylanthranilamides, recently reported by Yee et al. (J. Med. Chem., 43, 873-882), has been performed using principal component factor analysis as the preprocessing step. The study reveals that presence of electron-donating R2 substituent at the para position (with respect to the amide linkage) is conducive to the binding affinity, whereas a meta R2 substituent decreases the affinity. Again, electron-donating R1 substituents with less bulk and optimum hydrophilic-lipophilic balance (particularly, methyl and methoxy groups) favor the activity. The study further suggests that electron-withdrawing R3 substituents are detrimental for the activity, whereas bulkier R4 substituents (particularly NHSO2Me group) increase the activity.
    Drug Design and Discovery 02/2002; 18(1):23-31. DOI:10.1080/10559610213503
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    ABSTRACT: Recently, N2-aroylanthranilamides have been reported as novel series of possible anticoagulant drug candidates and the two aryl rings (A and B) have been suggested to interact with S1 and S4 regions, respectively, of human factor Xa (hfXa). In the present effort, quantitative structure-activity relationship (QSAR) of the hfXa binding affinity of 32 N2-aroylanthranilamides have been attempted, in continuation of our previous report on the QSAR analysis of the data set using linear free energy related (LFER) model, with electrotopological state atom (ETSA) index (Kier and Hall, 1991, Adv. Drug Design., 22, 1-38), to explore the atoms/regions of the compounds that modulate the activity comparatively to the greater extent. The univariate and bivariate relations involving the ETSA values of different common atoms of the compounds show importance of the atom nos. 12, 3 and 17 (arbitrary numbering): B ring carbon bearing meta R2 substituents, C ring carbon bearing R4 substituent, and carbonyl oxygen of A ring amide linkage. The importance of atom 12 is suggested to be due to detrimental effects of meta R2 substituents (B ring) on the hfXa binding affinity, which may be owing to interference in the attainment of the proper orientation of the phenyl ring in the S4 site. Atom 3 signifies the impact of R4 substituents (central C ring) on the binding affinity. Again, atom 17 (carbonyl oxygen of A ring amide linkage) has been suggested to form hydrogen bonding with the NH group of the other amide linkage, producing a pseudo ring and thus stabilizing the structure. The relations were improved further using indicator and physicochemical variables and the present results are in good agreement with the previous findings of the Hansch analysis.
    Drug Design and Discovery 02/2002; 18(1):33-43. DOI:10.1080/10559610213502
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    ABSTRACT: One hundred sixty-eight multiply substituted 1,4-benzodiazepines have been prepared by a five-step solid-phase combinatorial approach using syn-phase crowns as a solid support and a hydroxymethyl-phenoxy-acetamido linkage (Wang linker). The substituents of the 1,4-benzodiazepine scaffold have been varied in the -3, -5, -7, and 8-positions and the combinatorial library was evaluated in a chole cys to kinin (CCK) radioligand binding assay. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCK-B (CCK2) receptor have been optimized on the lipophilic side chain, the ketone moiety, and the stereochemistry at the 3-position. Various novel 3-alkylated compounds were synthesized and [S]3-propyl-5-phenyl-1,4-benzodiazepin-2-one, [S]NV-A, has shown a CCK-B selective binding at about 180 nM. Fifty-eight compounds of this combinatorial library were purified by preparative TLC and 25 compounds were isolated and fully characterized by TLC, IR, APCI-MS, and 1H/13C-NMR spectroscopy.
    Drug Design and Discovery 02/2002; 18(1):9-21. DOI:10.1080/10559610213504
  • G Olson ·

    Drug Design and Discovery 07/2001; 17(3):191.