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Results for “Designer Drugs”

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At least 163 records · Page 9Linked to original sources
PubMed1993

GroupBuild: a fragment-based method for de novo drug design.

A novel method for de novo drug design, GroupBuild, has been developed to suggest chemically reasonable structures which fill the active sites of enzymes. The proposed molecules provide good steric and electrostatic contact with the enzyme and exist in low-energy conformations. These structures are composed entirely of individual functional groups (also known as "building blocks" or "fragments") which the program chooses from a predefined library. User-selected enzyme seed atom(s) may be used to determine the area(s) in which structure generation begins. Alternatively, GroupBuild may begin with a predocked "inhibitor core" from which fragments are grown. For each new fragment generated by the program, several thousand candidates in a variety of locations and orientations are considered. Each of these candidates is scored based on a standard molecular mechanics potential function. The selected fragment and orientation are chosen from among the highest scoring cases. Tests of the method using HIV protease, FK506 binding protein, and human carbonic anhydrase demonstrate that structures similar to known potent inhibitors may be generated with GroupBuild.

Base Sequence↗
PubMed2004

De novo drug design: integration of structure-based and ligand-based methods.

Structure-based and ligand-based methods are used to derive predictive models in de novo drug design. Structure-based methods rely exclusively on prior knowledge of a protein structure to derive novel ligands, while ligand-based methods are traditionally used when no protein structure is available. Where there is sufficient information, these methods can be used in conjunction to increase the accuracy of simulation and enhance the drug design process. This review presents developments in the integration of these methods for de novo drug design, and recent results from both systems are highlighted.

Combinatorial Chemistry Techniques↗
PubMed2005

Crystallography for protein kinase drug design: PKA and SRC case studies.

Protein crystallography can be used throughout the drug discovery process to obtain diverse information critical for structure based drug design. At a minimum, a single target structure may be available. Optimally, and especially for protein kinases, a broad range of crystal structures should be obtained to characterize target flexibility, structure modulation via co-factor binding or posttranslational modification, ligand induced conformational changes, and off-target complex structures for selectivity optimization. The flexibility of the protein kinases is in contrast to the need for "crystallizable" constructs, that is, proteins that crystallize under varying conditions and in varying crystal packing arrangements. Strategies to produce crystallizable protein kinase constructs include truncation to the catalytic domain, co-crystallization with rigidifying ligands, crystallization of known rigid forms, and point mutation to improve homogeneity or mimic less crystallizable proteins. PKA, the prototypical serine/threonine protein kinase, and SRC, a tyrosine kinase and the first identified oncoprotein, provide multiple examples of these various approaches to protein kinase crystallography for drug design.

Animals↗
PubMed2005

Combining structure-based drug design and pharmacophores.

Development towards integrated computer-aided drug design methodologies is presented by utilising crystal structure complexes to produce structure-based pharmacophores. These novel pharmacophores represent the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The protein-ligand complexes can also yield information about all interactions that ligands could potentially form with the binding site, as well as about the size of the binding cavity. Together, these describe a 'superligand', which can also be viewed as a pharmacophore. Various types of novel pharmacophores are discussed and compared, using HIV-1 reverse transcriptase (RT) as the target protein, and their application in database searching is presented.

Binding Sites↗
PubMed2006

Homology modeling of G-protein-coupled receptors and implications in drug design.

G-protein-coupled receptors (GPCRs) are considered therapeutically important due to their involvement in a variety of processes governing several cellular functions, and their tractability as drug targets. A large percentage of drugs on the market, and in development stages, target the super family of the GPCRs. The enormous interest in GPCR drug design is, however, limited by the scarcity of structural information. The only GPCR for which a three dimensional (3D) structure is reported is bovine rhodopsin and it belongs to class A of the GPCR family. As a result, there has been considerable interest in alternative techniques, for example, homology modeling of GPCRs, in order to derive useful three dimensional models of other proteins for use in structure-based drug design. However, homology modeling of GPCRs is not straightforward, and encounters several problems, owing to the availability of a single structural template, as well as the low degree of sequence homology between the template and target sequences. There are several key issues which need to be considered during every stage of GPCR homology modeling, in order to derive reasonable 3D models. Homology modeling of GPCRs has been utilized increasingly in the past few years and has been successful, not only in furthering the understanding of ligand-protein interactions, but also in the identification of new and potent ligands. Thus, with the lessons learned from past experiences and new developments, homology modeling in case of GPCRs can be harnessed for developing more reliable three dimensional models. This, in turn, will provide better tools to use in structure-based drug design leading to the identification of novel and potent GPCR ligands for several therapeutic indications.

Amino Acid Sequence↗
PubMed2003

Optimization of antisense drug design against conservative local motif in simulant secondary structures of HER-2 mRNA and QSAR analysis.

AIM: To study the role of mRNA secondary structure stability in antisense drug design and obtain better antisense candidates against neu/HER-2/erbB-2 mRNA than previous report. METHODS: Program RNAstructure was utilized to simulate the secondary structures of HER-2 mRNA. Then 21 antisense phosphorothioate oligodeoxynucleotides (S-ODN) targeting different parts of secondary structural motif were designed. HA4 was set as positive control. Mean 50 % inhibitory effects (IC(50)) of S-ODN on proliferations of SK-BR-3 breast cancer cells were evaluated. The expression of target mRNA was detected by RT-PCR. The multiple regression and quantitative structure-activity relationship (QSAR) analysis was preformed by SPSS software. RESULTS: One optimal and two suboptimal secondary structures of target mRNA were obtained. Nine out of 11 S-ODN against completely conservative local motif (LM) (conservative among all simulant secondary structures) got lower or similar IC(50) values compared with HA4. On the other hand, 2 out of 3 S-ODN against relatively conservative LM (conservative between any two simulant secondary structures) got lower or similar IC(50) values compared with HA4. Only 2 out of 5 S-ODN targeting variable LM (variable among different predicted secondary structures) had acceptable activities. Average IC(50) of S-ODN against completely conservative LM was significantly lower than that of S-ODN against diverse LM. QSAR analysis suggested that stability, base number of bulge loops, and target free energies Delta GoT were statistically significant. In the multiple regression, R was 0.967, P=0.005. CONCLUSION: Antisense drug design against conservative LM was helpful for improving the positive rate. Several S-ODN candidates better than positive control were screened.

Antineoplastic Agents↗
PubMed2000

Designing drugs to stop the formation of prion aggregates and other amyloids.

Amyloid protein aggregates are implicated in many neurodegenerative diseases, including Alzheimer's disease and the prion diseases. Therapeutics to block amyloid formation are often tested in vitro, but it is not clear how to extrapolate from these experiments to a clinical setting, where the effective drug dose may be much lower. Here we address this question using a theoretical kinetic model to calculate the growth rate of protein aggregates as a function of the dose of each of three categories of drug. We find that therapeutics which block the growing ends of amyloids are the most promising, as alternative strategies may be ineffective or even accelerate amyloid formation at low drug concentrations. Our mathematical model can be used to identify and optimise an end-blocking drug in vitro. Our model also suggests an alternative explanation for data previously thought to prove the existence of an entity known as protein X.

Amyloid↗
PubMed2003

Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design.

The causative agent of severe acute respiratory syndrome (SARS) is a previously unidentified coronavirus, SARS-CoV. The RNA-dependent RNA polymerase (RdRp) of SARS-CoV plays a pivotal role in viral replication and is a potential target for anti-SARS therapy. There is a lack of structural or biochemical data on any coronavirus polymerase. To provide insights into the structure and function of SARS-CoV RdRp, we have located its conserved motifs that are shared by all RdRps, and built a three-dimensional model of the catalytic domain. The structural model permits us to discuss the potential functional roles of the conserved motifs and residues in replication and their potential interactions with inhibitors of related enzymes. We predict important structural attributes of potential anti-SARS-CoV RdRp nucleotide analog inhibitors: hydrogen-bonding capability for the 2' and 3' groups of the sugar ring and C3' endo sugar puckering, and the absence of a hydrophobic binding pocket for non-nucleoside analog inhibitors similar to those observed in hepatitis C virus RdRp and human immunodeficiency virus type 1 reverse transcriptase. We propose that the clinically observed resistance of SARS to ribavirin is probably due to perturbation of the conserved motif A that controls rNTP binding and fidelity of polymerization. Our results suggest that designing anti-SARS therapies can benefit from successful experiences in design of other antiviral drugs. This work should also provide guidance for future biochemical experiments.

Amino Acid Motifs↗
PubMedDate not supplied

Designing drugs.

Explore the source record for details and available documents.

Drug Design↗
PubMed2005

Designing drugs.

Explore the source record for details and available documents.

Antimetabolites, Antineoplastic↗
PubMed1997

The effects of unsaturated fatty acids, oxidizing agents and Michael reaction acceptors on the induction of N-ethylmaleimide reductase in Escherichia coli: possible application for drug design of chemoprotectors.

Menadione and dimethyl maleate, Michael reaction acceptors, induced N-ethylmaleimide (NEM) reductase activity in Escherichia coli strain DH5a. Linoleic acid also induced NEM reductase activity, but oleic acid, which is less susceptible to lipid peroxidation than linoleic acid, did not induce NEM reductase activity. In addition, NEM reductase activity was induced by menadione and linoleic acid also in strain DH5, Y1088 and Y1090. Linoleic acid is not a Michael reaction acceptor, but is known to produce Michael reaction acceptors such as alkenals and 4-hydroxyalkenals as a result of free-radical-initiated lipid peroxidation. Thus, our findings suggested that lipid peroxidation was involved in the induction of NEM reductase by linoleic acid. The electrophilic property of Michael reaction acceptors provides the signal for induction of phase II enzymes such as glutathione S-transferase and quinone reductase in mammals. The inducer potency of phase II enzymes has been used to design chemoprotective drugs. Therefore, the inducible nature of this enzyme will serve not only for the elucidation of its physiological function, but also for the evaluation of chemoprotective drugs.

Enzyme Induction↗
PubMedDate not supplied

[Designing drugs for transport into the brain].

This review focused on current of strategies for drug delivery to brain, including molecular modification, redox systems and liposomes. Particularly the transport through the blood-brain barrier relating to Parkinson's disease are being separately considered.

Animals↗
PubMed1992

Automated site-directed drug design using molecular lattices.

Receptor-based drug design is predicated on the knowledge of the structure of a target receptor and the principles of molecule recognition. The objective is to produce a wide diversity of structures that are sterically and electrostatically complementary to a specified receptor site. Many drug-receptor interactions are controlled by a few key receptor groups. This observation leads to a design approach in which one focuses on chemical fragments that putatively interact with the key receptor groups. There then remains the difficult task of joining the fragments into molecular structures that match the spatial patterns of recognition forces in the receptor site. In this paper, we describe a new modeling program, BUILDER, that combines database searching techniques and structure generation algorithms within an interactive graphics modeling environment (MidasPlus). A novel tool for process communication (delegate) is introduced and examples of its use are given. To demonstrate the functionality of the package and its ability to produce novel structures, we examine the active site of HIV-1 protease.

Algorithms↗
PubMed2002

AstexViewer: a visualisation aid for structure-based drug design.

AstexViewer is a Java molecular graphics program that can be used for visualisation in many aspects of structure-based drug design. This paper describes its functionality, implementation and examples of its use. The program can run as an Applet in a web browser allowing structures to be displayed without installing additional software. Applications of its use are described for visualisation and as part of a structure based design platform. The software is being made freely available to the community and may be downloaded from http://www.astex-technology.com/AstexViewer.

Computer Graphics↗