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PubMed2000

Rational selection of antisense oligonucleotide sequences.

The purpose of this review is to identify rational selection procedures for the identification of optimal antisense oligonucleotide sequences. The review is firstly focused on how to find optimal hybridization sites, and secondly on how to select sequences that bind to structured RNA. The methods reviewed range from the more empirical testing of large numbers of mRNA complementary sequences to the more systematic techniques, i.e. RNase H mapping, use of combinatorial arrays and prediction of secondary structure of mRNA by computational methods. Structures that bind to structured RNA, i.e. aptastrucs and tethered oligonucleotide probes, and foldback triplex-forming oligonucleotides are also discussed. Relating to selection of antisense sequences by aid of computational analysis, valuable www addresses are given along with examples of folded structures of mRNA.

Base Sequence↗
PubMed2001

A formal framework of knowledge to support rational psychoactive drug selection.

Rational psychoactive drug selection is a data and knowledge intensive task which requires true expertise from clinical, pathophysiological and pharmacotherapeutic knowledge. This paper presents a framework of knowledge, which relates concepts from several disciplines required for psychoactive drug selection in a formal way. A framework, when based on formal semantics, avoids ambiguity and gives conceptual clarity and supports precise use of terminology which is required when many domain experts (clinicians, pharmacologists and basic science researchers) are involved. A formal framework permits linking of existing classification systems. It furthermore can serve as a knowledge base for drug selection decision support systems.

Artificial Intelligence↗
PubMed2000

Rational antigen modification as a strategy to upregulate or downregulate antigen recognition.

Recent and rapid advances in our understanding of the cellular and molecular mechanisms of antigen recognition by CD8(+) and CD4(+) T lymphocytes have led to the birth of possibilities for site-directed, rational modification of cognate antigenic determinants. This immunologic concept has vast biomedical implications for regulation of host immunity against the pathogenesis of diverse disease processes. The upregulation of antigen-specific T-cell responses by 'agonistic' peptides would be most desirable in response to invasive pathogenic challenges, such as infectious and neoplastic disease, while the downregulation of antigen-specific T-cell responses by 'antagonistic' peptides would be most efficacious during inappropriate pathologic consequences, such as autoimmunity. The capacity to experimentally manipulate intrinsic properties of cognate peptide ligands to appropriately alter the nature, course and potency of cellular immune interactions has important potential in both preventive and therapeutic clinical paradigms.

Animals↗
PubMed2001

A rationally designed oligopeptide shows significant conformational changes upon binding to sulphate ions.

Oligopeptides that interact with oxoanions were developed by rational design methods. The substrate-binding site of the enzyme purine nucleoside phosphorylase served as a model for the design of the ionophores. The amino acids involved in the complexation of oxoanions were linked through flexible spacer residues. These spacers were chosen such that the relative orientation of the interacting amino acids was conserved. Several peptide sequences were preselected based on intermolecular H-bond frequencies. These frequencies were calculated from molecular dynamics trajectories of the corresponding peptide-anion complexes and used to score the binding properties of the peptides. The most promising peptides were prepared using solid phase peptide synthesis. Anion binding of the peptide ionophores was screened using circular dichroism (CD) and confirmed by NMR spectroscopy. CD measurements performed in methanol revealed a significant conformational change of a linear undecapeptide upon binding to sulphate ions. Two-dimensional-NMR experiments confirmed that a conformation with high helical content is formed in the presence of sulphate ions. These conformational changes induced by the anion stimulate the development of new transduction mechanisms in chemical sensors.

Amino Acid Sequence↗
PubMed1998

Engineering multi-domain redox proteins containing flavodoxin as bio-transformer: preparatory studies by rational design.

This work demonstrates that non-physiological electron transfer (ET) can occur in solution between wild type D. vulgaris flavodoxin (Fld) and horse heart cytochrome c (cyt-c), D. vulgaris cytochrome c553 (cyt-c553) and the haem domain of B. megaterium cytochrome P450 (cyt-P450 BMP). Second order rate constants of the ET reaction between [Fld]sq/[cyt-c]ox, [Fld]sq/[cyt-c553]ox and [Fld]sq/[cyt-P450 BMP]ox, were found to be 6.16 x 10(5), 1.80 x 10(4) and in the region of 10(5) respectively. These data are interpreted in terms of complementarity between the surfaces of the two proteins, their surface and redox potentials. Analysis of the ET results obtained from the separate wild type proteins supported the rational design approach in the creation of Fld-based chimeras. The preliminary design of the chimeras reported here is a 3D prototype for an artificial flavo-cytochrome obtained by covalent linkage of a Fld module to cyt-c553 via a disulphide bond. Theoretical ET rates calculated on the modelled flavo-cytochrome are encouraging the construction of these chimeric systems at DNA level. This work is now underway. The relevance of this molecular lego approach is to be seen in the long term goal of producing engineered multi-domain systems to be applied in the field of biosensors and bioelectronics to fulfil specific requirements. Novel catalytic devices can be obtained by using natural redox proteins in different combinations: this process mimics the natural evolution of proteins such as gene shuffling and gene fusion.

Animals↗
PubMed2002

Rational development of capecitabine.

Capecitabine is a fluoropyrimidine carbamate that was rationally designed as an oral drug capable of mimicking continuous infusion 5-fluorouracil (5-FU) and delivering 5-FU preferentially to tumour tissue. Following extensive absorption, capecitabine is rapidly converted to 5-FU via a three-step enzymatic pathway. The final step depends on thymidine phosphorylase, an enzyme present at higher concentrations in malignant compared with normal tissue. This results in the delivery of 5-FU preferentially to the tumour site. Capecitabine has demonstrated high activity in preclinical xenograft models for a wide range of human solid tumours, including those resistant to 5-FU. Phase I studies have determined the maximum tolerated dose (MTD) of capecitabine and identified a number of dosage regimens, which were subsequently evaluated in a randomised, phase II study as first-line treatment for metastatic colorectal cancer. This established an intermittent regimen of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period as the most appropriate regimen for further clinical development.

Administration, Oral↗
PubMed1998

Overview of a rational approach to design type I 17beta-hydroxysteroid dehydrogenase inhibitors without estrogenic activity: chemical synthesis and biological evaluation.

Hormone-sensitive diseases such as breast cancer are health problems of major importance in North America and Europe. Endocrine therapies using antiestrogens for the treatment and the prevention of breast cancer are presently under clinical trials. Antiestrogens are drugs that compete with estrogens for the estrogen receptor without activating the transcription of estrogen-sensitive genes. However, an optimal blockade of estrogen action could ideally be achieved by a dual-action compound that would antagonize the estrogen receptor and inhibit the biosynthesis of estradiol. Type I 17beta-hydroxysteroid dehydrogenase (17beta-HSD) was chosen as a key steroidogenic target enzyme to inhibit the formation of estradiol, which is the most potent estrogen. This article describes a rational approach that could lead to the development of compounds that exhibit both actions. The chemical syntheses of estradiol derivatives bearing a bromoalkyl and a bromoalkylamide side chain at the 16alpha-position are summarized. Two parameters were studied for biological evaluation of our synthetic inhibitors: (1) the inhibition of estrone reduction into estradiol by type I 17beta-HSD, and (2) the proliferative/antiproliferative cell assays performed on the estrogen-sensitive ZR-75-1 breast tumor cell line. First, the substitution of the 16alpha-position of estradiol by bromoalkyl side chain led to potent inhibitors of type I 17beta-HSD, but the estrogenic activity remained. Secondly, an alkylamide functionality at the 16alpha- or 7alpha-position of estradiol cannot abolish the estrogenic activity without affecting considerably the inhibitory potency on type I 17beta-HSD. In conclusion, the best dual-action inhibitor synthesized showed an IC50 of 13 +/- 1 microM for type I 17beta-HSD, while displaying antiestrogenic activity at 1.0 microM. Despite the fact that we did not obtain an ideal dual-action blocker, we have optimized several structural parameters providing important structure-activity relationship.

17-Hydroxysteroid Dehydrogenases↗
PubMed2000

Treatment of experimental allergic encephalomyelitis (EAE) by a rationally designed cyclic analogue of myelin basic protein (MBP) epitope 72-85.

In this report the rational design, synthesis and pharmacological properties of an amide-linked cyclic antagonist analogue of the guinea pig myelin basic protein epitope MBP(72-85) are described. Design of the potent cyclic analogue was based on 2D NOESY nuclear magnetic resonance and molecular dynamics studies carried out in the linear antagonist Ala81MBP(72-85). The cyclic antagonist completely prevented the induction of experimental allergic/autoimmune encephalomyelitis when coinjected with linear and cyclic agonist analogues MBP(72-85) and cyclo(2-9)MBP(72-85).

Animals↗
PubMed2001

Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth.

In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.

Antineoplastic Agents↗
PubMed2001

Rational design and synthesis of novel 2,5-disubstituted cis- and trans-piperidine derivatives exhibiting differential activity for the dopamine transporter.

Herein, we report the rational design and synthesis of novel 2,5-disubstituted piperidine derivatives in the cis and trans isomeric forms. Out of these two isomers, the cis-isomer, 7a, was found to exhibit the most potent activity and selectivity for the dopamine transporter. These novel derivatives represent conformationally constrained version of piperidine analogue of GBR compounds.

Benzhydryl Compounds↗
PubMed2002

alpha(1)-Adrenoceptor antagonists. Rational design, synthesis and biological evaluation of new trazodone-like compounds.

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus.

The novel thiourea compound N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) targeting the non-nucleoside inhibitor (NNI) binding pocket of HIV-1 reverse transcriptase (RT) was rationally designed using a computer model of the NNI binding pocket. The NNI binding pocket model takes into consideration changes in binding pocket size, shape, and changes in residue character that result from clinically-observed NNI resistance-associated mutations of HIV RT. RT assays revealed that HI-236 was not only more potent than trovirdine, MKC-442, and AZT against the drug-sensitive HIV-1 strain HTLV(IIIB), it was also 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. Most importantly, HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR with multiple mutations involving the RT residues 74V, 41L, 106A, and 215Y. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, which are listed in the following order: HI-236 (IC50: 5 nM) > HI-240 (IC50: 6 nM) > trovirdine (IC50: 20 nM) > AZT (IC50: 150 nM) > MKC-442 (IC50: 300 nM) > delavirdine (IC50: 400 nM) > nevirapine (IC50: 5 microM).

Anti-HIV Agents↗
PubMed2000

In silico studies for the rational discovery of anticonvulsant compounds.

Theoretical models to virtual screening and rational design of anticonvulsant compounds based on a topological substructural molecular design (TOSS-MODE) approach are developed. These models, developed on the basis of data sets of great structural variability, permit the classification of compounds as active/inactive anticonvulsants and predict the quantitative anticonvulsant potency of such compounds. The classification model is applied to a virtual screening of anticonvulsant compounds by analyzing a data set of molecules reported in the literature. More than 88% of them were well classified by the current model. Active and inactive fragments are identified by using the present approach. Some of the active fragments are identified in anticonvulsant molecules as potential pharmacophores and one of them is analyzed in detail. The three-dimensional (3-D) features of this fragment are investigated in a series of five anticonvulsant compounds. Some structure-anticonvulsant activity relationships are derived on the basis of the 3-D structure of this fragment and some findings reported in the literature that indicate that it is an important pharamacophore are outlined.

Anticonvulsants↗
PubMed1994

Rational design of high affinity tachykinin NK2 receptor antagonists.

The rational discovery of a high affinity NK2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK2 receptor binding affinity for each amino acid of the hexapeptide 'minimum fragment': Leu-Met-Gln-Trp-Phe-GlyNH2 (8c), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an 'alanine scan'. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH2 (9a) is a micromolar affinity NK2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK2 receptor antagonist, (2,3di-CH3OPh)CH2OCO(S)Trp(S)alpha-MePheGlyNH2, PD 147714 (19) with an K(i) = 1.4 nM (hamster urinary bladder membranes and using [125I]-iodohistidyl-NKA (0.1 nM) as the radioligand).

Amino Acid Sequence↗
PubMed1994

Rational design of high affinity tachykinin NK1 receptor antagonists.

The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv.

Animals↗
PubMed1998

Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reserve transcriptase.

A series of novel phenethylthiazolylthiourea (PETT) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket. The structure-based design and synthesis of these new PETT derivatives were complemented by biological assays of their anti-HIV activity. Modeling studies for rational drug design included the construction of a composite NNI binding pocket from nine RT-NNI crystal structures, the analyses of surface complementarity between NNI and RT, and application of Ki calculations combined with a docking procedure involving the novel PETT derivatives. The use of the composite NNI binding pocket allowed the identification and structure-based design of three promising PETT derivatives with ortho-F (2), ortho-Cl (3), and meta-F (5) substituents on the phenyl ring. These novel PETT derivatives were more active than AZT or trovirdine and showed potent anti-HIV activity with IC50[p24] values of < 1 nM and selectivity indices of > 100,000.

Anti-HIV Agents↗
PubMed2002

Graves' ophthalmopathy: a rational approach to treatment.

The past decade has witnessed great progress in our understanding of Graves' opthalmopathy (GO), although its precise immunopathogenesis remains an enigma. Several clinical studies have provided a more rational basis for treatment of this distressing disease, which significantly lowers the quality of life. A management plan tailored to the patient's needs can be devised according to the severity and activity of the eye disease. In active GO, immunosuppression might be considered. The combination of intravenous pulses of methylprednisolone and retrobulbar irradiation improves eye changes in 88% of patients, and is well tolerated. Once the disease has become inactive, rehabilitative surgery could be performed (orbital decompression, strabismus surgery and eyelid surgery, in that order). The patient should be reassured that functional and cosmetic improvement of eye changes is feasible, but restoration can require one to two years. To a certain extent, refraining from smoking prevents the development or worsening of GO.

Combined Modality Therapy↗