Search results for "Drug Design"
showing 10 items of 232 documents
Structural invariants for the prediction of relative toxicities of polychloro dibenzo-p-dioxins and dibenzofurans
2004
Multivariate models are reported that can predict the relative toxicity of compounds with severe environmental impact, namely polychloro dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). Multiple linear regression analysis (MLR) and partial least square projections of latent variables (PLS) show the usefulness of graph-theoretical descriptors, mainly topological charge indices (TCIs), in these series. The general trends of the group are correctly reproduced and better results are presented than have previously been published. In general, the more toxic compounds exhibit more symmetric molecular structures.
Novel inhibitors in development for hepatocellular carcinoma
2010
The multikinase inhibitor sorafenib was the first agent to demonstrate a survival benefit for patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Although sorafenib represents a landmark in the treatment of HCC and proved molecularly targeted therapy to be effective in this disease, it represents just the first step towards an improvement in systemic therapy. Since then, novel inhibitors have been evaluated in early clinical trials, showing potential activity.This article aims to review novel inhibitors emerging in the field of advanced HCC. An Internet-based search was performed to identify abstracts, clinical trials ( www.clinicaltrials.gov , last accessed 30 Nove…
BANΔIT: B’‐factor Analysis for Drug Design and Structural Biology
2020
The analysis of B‐factor profiles from X‐ray protein structures can be utilized for structure‐based drug design since protein mobility changes have been associated with the quality of protein‐ligand interactions. With the BANΔIT (B’‐factor analysis and ΔB’ interpretation toolkit), we have developed a JavaScript‐based browser application that provides a graphical user interface for the normalization and analysis of B’‐factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein‐ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B’‐factor‐supported pha…
Designing robust immediate release tablet formulations avoiding food effects for BCS class 3 drugs
2019
Abstract Food induced viscosity in the gastrointestinal tract is reported to reduce the bioavailability of tablets containing BCS class 3 drugs, mainly by retarding their disintegration and dissolution of the active pharmaceutical ingredient. The role of formulation factors in minimizing this negative food effect is largely unknown. Combinations of disintegrants were studied together with soluble and insoluble fillers and trospium chloride as model drug substance. Different batches of tablets were compressed at 10 kN and 30 kN, by incorporating different combinations of croscarmellose sodium (CSS), cross-linked (CPD) and sodium starch glycolate (SSG) at low level i.e, 2% + 2% and high level…
Looking for a new panacea in ALK-rearranged NSCLC: may be Ceritinib?
2014
Abstract: In the past decade, the advent of targeted therapy led to a silent revolution in the war against lung cancer and a significant evolution on the concept of Phase I clinical trials design. Thanks to the specificity of their target, the new drugs have radically changed NSCLC treatment, leading to the development of personalized strategies. The accelerated approval of the first ALK-inhibitor, Crizotinib and more recently Ceritinib, without a Phase III randomized, clinical trial, has been an amazing success story in lung cancer research, marking the beginning of a new decade of targeted drugs development, characterized by modern, biomarker-driven, early clinical trial design and shorte…
Therapeutic targets for overactive bladder other than smooth muscle
2015
For a long time, our concepts of regulation of urinary bladder function in health and disease as well as of the target structures of therapeutics have focused on detrusor smooth muscle cells. However, other structures including urothelium, afferent nerves and bladder blood vessels may also be important in pathophysiology and its treatment.Based on a selective review of literature, we discuss the role of urothelium, afferent nerve fibers and bladder blood vessels in bladder pathophysiology and as targets for treatment.There is solid evidence now that multiple anatomical structures within the urinary bladder contribute to the regulation of its function and hence may be targets for established…
Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma-a rationale for a molecular targeting strategy?
2007
AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma. METHODS: The (co-)expression pattern of VEGFR1-3, PDGFRα/β and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFRα (82%) and PDGFRβ (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRα revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additiona…
Discovery of new antimalarial compounds by use of molecular connectivity techniques.
1999
Abstract Molecular connectivity has been applied to the search for new compounds with antimalarial activity. Linear discriminant analysis and connectivity functions were used to select several potentially suitable drugs which were tested for antimalarial properties by use of an in-vitro micro test which estimates parasite growth by measurement of incorporation of [3H]hypoxanthine. Hexetidine stands out among the compounds selected. Activity assays were performed with Plasmodium falciparum passou and 3CD7 strains, for which the IC50 values (doses resulting in 50% inhibition) were 320 and 400 ng mL−1 respectively. These results are comparable with those obtained for quinine chlorhydrate (IC50…
Advances in Marine Natural Products of the Indole and Annelated Indole Series: Chemical and Biological Aspects
2001
Marine natural products, form a field of scientific endeavour, that has recently grown considerably. The isolation, biological evaluation, chemical properties and synthetic elaborations of products of marine organisms have attracted the attention of organic chemists, medicinal chemists, biologists and pharmacists. In this context a structurally and biologically highly interesting class is represented by the marine natural products containing an indole moiety in a pure substituted form or in an anellated form. The present review summarizes primarily the actual results concerning these products as new pharmacologically attractive lead compounds for drug design. The chemistry, biological evalu…
New agents active against Mycobacterium avium complex selected by molecular topology: a virtual screening method
2003
Objectives: In order to select new drugs and to predict their in vitro activity against Mycobacterium avium complex (MAC), new quantitative structure-activity relationship (QSAR) models were developed. Methods: The activities against MAC of 29 structurally heterogeneous drugs were examined by means of linear discriminant analysis (LDA) and multilinear regression analysis (MLRA) by using topological indices (TI) as structural descriptors. In vitro antimycobacterial activities were determined by a broth microdilution method with 7H9 medium. Results: The topological model obtained successfully classifies over 80% of compounds as active or inactive; consequently, it was applied in the search fo…