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PubMed2004

A rational approach to maximize success rate in target discovery.

To overcome the problem of high attrition rates in the drug discovery process, an efficient strategy how to identify, select, characterize and validate the most suitable drug targets before embarking on the resource-intense steps of lead discovery and lead optimization is mandatory. We have implemented such an efficient strategy consisting of (i) Target Selection based on gene expression analyses of drugable target genes in clinical samples and relevant in vitro model systems, to identify candidate targets with a specific tissue distribution and presence in human disease; (ii) Target Assessment exploiting the three-dimensional structure of proteins for detailed binding site analysis, to estimate the drugability of the protein for small-molecule inhibitor binding as well as selectivity profiles; and (iii) Target Validation providing evidence for a functional role in in vitro model systems, thus corroborating the biological hypothesis underlying the therapeutic concept. This rational approach has led to the discovery of drug targets for Lead Discovery, maximizing the likelihood for achieving target-selective inhibition by small-molecule inhibitors with minimal in vivo side effects and a therapeutic effect based on a sound biological hypothesis.

Binding Sites↗

PubMed2006

Rational design and synthesis of a double-stranded DNA-binder library.

Described is a computer-assisted rational design of a DNA-bis-intercalator peptide library. The peptide library of 250 members was prepared and the most powerful binder identified. A value of the binding constant is almost two orders of magnitude higher than that of starting building block-9-aminoacridine. The binder affinity found toward calf thymus DNA is 30-fold of that of human prion peptide 106-126.

Aminacrine↗

PubMed2002

Metabolic pathway analysis of a recombinant yeast for rational strain development.

Elementary mode analysis has been used to study a metabolic pathway model of a recombinant Saccharomyces cerevisiae system that was genetically engineered to produce the bacterial storage compound poly-beta-hydroxybutyrate (PHB). The model includes biochemical reactions from the intermediary metabolism and takes into account cellular compartmentalization as well as the reversibility/irreversibility of the reactions. The reaction network connects the production and/or consumption of eight external metabolites including glucose, acetate, glycerol, ethanol, PHB, CO(2), succinate, and adenosine triphosphate (ATP). Elementary mode analysis of the wild-type S. cerevisiae system reveals 241 unique reaction combinations that balance the eight external metabolites. When the recombinant PHB pathway is included, and when the reaction model is altered to simulate the experimental conditions when PHB accumulates, the analysis reveals 20 unique elementary modes. Of these 20 modes, 7 produce PHB with the optimal mode having a theoretical PHB carbon yield of 0.67. Elementary mode analysis was also used to analyze the possible effects of biochemical network modifications and altered culturing conditions. When the natively absent ATP citrate-lyase activity is added to the recombinant reaction network, the number of unique modes increases from 20 to 496, with 314 of these modes producing PHB. With this topological modification, the maximum theoretical PHB carbon yield increases from 0.67 to 0.83. Adding a transhydrogenase reaction to the model also improves the theoretical conversion of substrate into PHB. The recombinant system with the transhydrogenase reaction but without the ATP citrate-lyase reaction has an increase in PHB carbon yield from 0.67 to 0.71. When the model includes both the ATP citrate-lyase reaction and the transhydrogenase reaction, the maximum theoretical carbon yield increases to 0.84. The reaction model was also used to explore the possibility of producing PHB under anaerobic conditions. In the absence of oxygen, the recombinant reaction network possesses two elementary modes capable of producing PHB. Interestingly, both modes also produce ethanol. Elementary mode analysis provides a means of deconstructing complex metabolic networks into their basic functional units. This information can be used for analyzing existing pathways and for the rational design of further modifications that could improve the system's conversion of substrate into product.

ATP Citrate (pro-S)-Lyase↗

PubMed1988

A rational technique for surgical operation on Borrmann type 4 gastric carcinoma: left upper abdominal evisceration plus Appleby's method.

Borrmann type 4 gastric carcinoma, including linitis plastica, is difficult to detect at an early stage and the results of surgical treatment remain poor. We have used 'left upper abdominal evisceration plus Appleby's method (LUAE + Apl.)' as a radical surgical procedure for this disease. During the period 1983-86, 30 cases of Borrmann type 4 gastric carcinoma underwent this procedure (Group A). These cases were compared with 30 patients who underwent total gastrectomy with pancreaticosplenectomy (Group B) during the period 1980-82. Although this is not a randomized study and the extent of resection was greater in Group A, the operation time, amount of blood loss, and number of complications were similar for both methods. When the survival rates were compared, the 3-year survival rate in stage II-III cases was higher for Group A (83.3 per cent) than for Group B (42.2 per cent) (P less than 0.05). One patient in Group A and 12 patients in Group B died with peritoneal metastasis within 3 years of operation in stage II-III. The LUAE + Apl. method is a rational and useful technique for the surgical treatment of Borrmann type 4 gastric carcinoma.

Adult↗

PubMed1989

Computer analysis in making preoperative decisions: a rational approach to lymph node dissection in gastric cancer patients.

In Japan, R2 lymph node dissection is standard practice for all curatively resected gastric cancer patients. From 1969 to 1984, data were collected prospectively to evaluate this procedure and to provide information for a more rational approach to node dissection for each individual case. A total of 3843 cases was included in this study and an evaluation was made of the prognostic variables and lymph node involvement at various locations. Using a computer program, it is possible to compile a group of treated patients, with prognostic variables exactly matching those of an individual patient. Analysis of this group can then give an indication of the extent of lymph node dissection required for an individual patient. This paper gives a demonstration of the structure of such a system by means of an example.

Decision Making, Computer-Assisted↗

PubMed2005

Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

Drug Design↗

PubMed2004

Addressing the challenge of changing the specificity of RNase T1 with rational and evolutionary approaches.

Although ribonuclease T1 (RNase T1) is one of the best-characterized proteins with respect to structure and enzymatic action, numerous attempts at altering the specificity of the enzyme to cleave single-stranded RNA at the 3'-side of adenylic instead of guanylic residues by rational approaches have failed so far. Recently we generated and characterized the RNase T1 variant RV with a 7200-fold increase in adenylyl-3',5'-cytidine (ApC)/guanylyl-3',5'-cytidine (GpC) preference, with the guanine-binding loop changed from 41-KYNNYE-46 (wt) to 41-EFRNWN-46. Now we have introduced the asparagine residue at position 46 of the wild-type enzyme as a single-point mutation in variant E46N and in combination with the Y45W exchange also occurring in RV. Both variants show an improved ApC/GpC preference with a 1450-fold increase for E46N and a 2100-fold increase for Y45W/E46N in comparison to wild-type activity. We also addressed the challenge of altering enzyme specificity with an evolutionary approach. We have randomly introduced point mutations into the RNase T1 wild-type gene and into the gene of the variant RV with different mutation rates. Altogether we have screened about 100,000 individual clones for activity on RNase indicator plates; 533 of these clones were active. A significant change in substrate specificity towards an ApC preference could not be observed for any of these active variants; this demonstrated the magnitude of the challenge to alter the specificity of this evolutionary perfected enzyme.

Amino Acids↗

PubMed2005

Exploring the active-site of a rationally redesigned lipase for catalysis of Michael-type additions.

Michael-type additions of various thiols and alpha,beta-unsaturated carbonyl compounds were performed in organic solvent catalyzed by wild-type and a rationally redesigned mutant of Candida antarctica lipase B. The mutant lacks the nucleophilic serine 105 in the active-site; this results in a changed catalytic mechanism of the enzyme. The possibility of utilizing this mutant for Michael-type additions was initially explored by quantum-chemical calculations on the reaction between acrolein and methanethiol in a model system. The model system was constructed on the basis of docking and molecular-dynamics simulations and was designed to simulate the catalytic properties of the active site. The catalytic system was explored experimentally with a range of different substrates. The kca values were found to be in the range of 10(-3) to 4 min(-1), similar to the values obtained with aldolase antibodies. The enzyme proficiency was 10(7). Furthermore, the Michael-type reactions followed saturation kinetics and were confirmed to take place in the enzyme active site.

Binding Sites↗

PubMed2004

Rational design of the first closed coordination capsule with octahedral outer shape.

The rational synthesis of an octahedral coordination capsule in which the triangular faces are covered by single ligands is described herein. Starting with tris(2-hydroxybenzylidene)triaminoguanidinium chloride [H(6)L]Cl, we observed an oxidative cyclization of this ligand in the presence of PPh(4) (+) ions resulting in the complex [Pd(H(2)L')(PPh(3))] (1). The use of 5,5-diethylbarbiturate (bar(2-)) as a bridging ligand in the presence of [Co(en)(3)](3+) (en=ethylenediamine) leads to the formation of a rectangular box with the formula (Et(4)N)(6)[[Co[(PdCl)(Pd)L](2)(mu-bar)](2)] (2). The analysis of the architecture of compounds 1 and 2 enables the development of a self-assembly strategy for the synthesis of an octahedral coordination cage 3 with the formula Na(4)(Et(3)NH)(12)[(Pd(3)L)(8)[mu-(bar)](12)].x H(2)O. Compound 3 was characterized by (13)C-MAS-NMR spectroscopy and single-crystal structure analysis.

Journal Article↗

PubMed2004

Combinatorial chemistry approach to chiral catalyst engineering and screening: rational design and serendipity.

An efficient asymmetric catalyst relies on the successful combination of a large number of interrelated variables, including rational design, intuition, persistence, and good fortune-not all of which are necessarily well-understood; this renders such practice largely empirical. As a result, the possibility of using combinatorial chemistry methods in asymmetric catalysis research has been widely recognized to be highly desirable. In this account, we attempt to show the principle and application of combinatorial approach in the discovery of chiral catalysts for enantioselective reactions. The concept focuses on the strategy for the creation of a modular chiral catalyst library by two-component ligand modification of metal ions on the basis of molecular recognition and assembly. The self-assembled chiral catalyst with two different ligands indeed exhibited synergistic effects in terms of both enantioselectivity and activity in comparison with its corresponding homocombinations in many reactions. The examples described in this paper demonstrated the powerfulness of combinatorial approach for the discovery of novel chiral catalyst systems, particularly for the development of highly efficient, enantioselective, and practical catalysts for enantioselective reactions. We hope this concept will stimulate further work on the discovery of more highly efficient and enantioselective catalysts, as well as unexpected classes of catalysts or catalytic enantioselective reactions in the future with the help of a combinatorial chemistry approach.

Catalysis↗

PubMed2003

Substituent effects on O--H bond dissociation enthalpies and ionization potentials of catechols: a DFT study and its implications in the rational design of phenolic antioxidants and elucidation of structure-activity relationships for flavonoid antioxidants.

Density functional theory (DFT) on B3LYP/6-31G(d,p) level was employed to investigate the substituent effects on O--H bond dissociation enthalpies (BDEs) and ionization potentials (IPs) of catechols. It was revealed that the ortho hydroxyl of catechol was effective for the reduction of the O--H BDE; however, the group had little influence on the IP. The para substituent effects upon O--H BDEs and IPs for catechols were roughly the same as those for monophenols, and this gave the catechol moiety more potential than monophenol to be used as a lead compound in rational design of phenolic antioxidants. In addition, the 1,4-pyrone effects on O--H BDEs of catecholic rings A or B of flavonoids were also investigated. Although 1,4-pyrone extended the conjugation system of flavonoids, it was not beneficial to reduce the O--H BDE as a result of its electron-withdrawing property. Thus, 1,4-pyrone was unlikely to be favorable to enhance the H-abstraction activity of flavonoids.

Antioxidants↗

PubMed2004

Rational design of the pore system within the framework aluminium alkylenediphosphonate series.

We report here on the solvothermal synthesis and crystal structure of the hybrid organic-inorganic framework material Al(2)[O(3)PC(3)H(6)PO(3)](H(2)O)(2)F(2).H(2)O (orthorhombic, Pmmn, a = 12.0591(2) A, b = 19.1647(5) A, c = 4.91142(7) A, Z = 4), the second member of the Al(2)[O(3)PC(n)H(2n)PO(3)](H(2)O)(2)F(2).H(2)O series. The structure consists of corrugated chains of corner-sharing AlO(4)F(2) octahedra in which alternating AlO(4)F(2) octahedra contain two fluorine atoms in a trans or a cis configuration. The diphosphonate groups link the chains together through Al-O-P-O-Al bridges and through the propylene groups to form a three-dimensional framework structure containing a one-dimensional channel system. The linkage of the corrugated inorganic Al-O-P layers within the structure results in the formation of two types of channel that differ in size, shape and composition. The smaller channel is unoccupied; the larger channel is more elongated and contains two extra-framework water molecules per unit cell. A computational investigation into the driving force that controls the stacking arrangement of the Al-O-P inorganic layers within this series of compounds reveals that the stacking is found to be controlled by thermodynamic factors, arising chiefly from the conformation of the organic linker molecule used to connect the inorganic sheets. It is found that the registration of the inorganic layers can be engineered by selecting an appropriate, simple organic spacer or linker alkyl chain, where an even number of carbon atoms in the alkyl chain directs formation of aligned, stacked, inorganic sheets (AAAAAA), and an odd number directs formation of unaligned, stacked sheets (ABABAB) and the formation of one or two channel types in the resultant structure, respectively. This combination of alkyl-chain linkers in conjunction with corrugated inorganic layers is an effective tool to rationally design the pore system of hybrid framework materials.

Journal Article↗

PubMed2004

Rationally functionalized deltahedral zintl ions: synthesis and characterization of [Ge9-ER3]3-, [R3E-Ge9-ER3]2-, and [R3E-Ge9-Ge9-ER3]4- (E=Ge, Sn; R=Me, Ph).

Six new derivatized deltahedral Zintl ions have been synthesized by reactions between the known Zintl ions Ge(9) (n-) with the halides R(3)EX and/or the corresponding anions R(3)E(-) for E=Ge or Sn. This rational approach is based on our previous discovery that these derivatization reactions are based on nucleophilic addition to the clusters. All species were structurally characterized as their salts with potassium countercations sequestered in 2,2,2-crypt or [18]crown-6 ether. The tin-containing anions were characterized also in solutions by (119)Sn NMR spectroscopy. The reaction types for such substitutions and the structures of the new anions are discussed.

Journal Article↗

PubMed2005

Study of the growth of capped ZnO nanocrystals: a route to rational synthesis.

We report the study of complex and unexpected dependencies of nanocrystal size as well as nanocrystal-size distribution on various reaction parameters in the synthesis of ZnO nanocrystals using poly(vinyl pyrollidone) (PVP) as a capping agent. This method establishes a qualitatively different growth mechanism to the anticipated Ostwald ripening behavior. The study of size-distribution kinetics and an understanding of the observed non-monotonic behaviors provides a route to rational synthesis. We used a simple, but accurate, approach to estimate the size-distribution function of nanocrystals from the UV-absorption spectrum. Our results demonstrate the accuracy and generality of this approach, and we also illustrate its application to various semiconducting nanocrystals, such as ZnO, ZnS, and CdSe, over a wide size range (1.8-5.3 nm).

Journal Article↗

PubMed2007

Rational design of sterically and electronically easily tunable chiral bisimidazolines and their applications in dual Lewis acid/brønsted base catalysis for highly enantioselective nitroaldol (Henry) reactions.

A new addition to the rational design of sterically and electrically easily tunable chiral bis(imidazoline) ligands from chiral amino alcohols has been developed. Vast structural variation of chiral bis(imidazoline) ligands can be simply achieved by the choice of both the 1,2-amino alcohol and its N-1 R1 substituent. A small library of chiral bisimidazolines (1 a-h) has been constructed. The method has provided an easy and simplified route to a diverse set of air-stable and water-tolerant chiral bis(imidazoline) ligands on 10 g scales. The dual Lewis Acid/Brønsted base catalytic system generated from the (S)-1 a/Cu(OTf)2 complex and Et3N was able to catalyze Henry reactions between aldehydes and nitromethane effectively at room temperature, and also to tolerate a wide scope of aldehydes with excellent enantiomeric excesses. Not only aromatic aldehydes but also aliphatic aldehydes afforded the nitroalcohol products, with enantiomeric excesses in the 93-98% range. This dual catalytic system is among the most effective systems so far reported for the asymmetric parent Henry reactions. This work also represents the first members of the class of chiral bisimidazolines to have been demonstrated to achieve excellent enantioselectivities.

Acids↗

PubMed2001

Supramolecular chirality induction in bis(zinc porphyrin) by amino acid derivatives: rationalization and applications of the ligand bulkiness effect.

The achiral syn conformer (face-to-face) of the ethane-bridged bis(zinc porphyrin) (syn-ZnD) transforms into the corresponding chiral extended anti bis-ligated species (anti-ZnD.L2) in the presence of enantiopure ligands (L: amino acid derivatives). The mechanism of the supramolecular chirality induction is based on chiral ligand binding to zinc porphyrins and subsequent formation of either right- or left-handed screw structures in anti-ZnD.L2. The screw structure formation arises from steric interactions between the bulkiest substituent at the asymmetric carbon of the ligand and the peripheral ethyl groups of the neighboring porphyrin ring directed towards the covalent bridge. The sign and amplitude of the induced circular dichroism (CD) are dependent on the steric bulk of the substituents at the chiral center. The greater difference in size between the chiral center's substituents gives the stronger induced CD signal. Rationalization of the ligand bulkiness effect on chirality induction by amino acid derivatives, application of this supramolecular system for the determination of ligand absolute configuration, and relative bulkiness of the substituents at the asymmetric carbon are discussed.

Journal Article↗

PubMed1991

Developing a rational management strategy for angina pectoris after coronary bypass surgery: a clinical decision analysis.

Long-term follow-up of patients undergoing coronary artery bypass graft surgery indicates that as many as 50% eventually experience recurrent angina pectoris. Rational management of these individuals requires an understanding of the natural history of coronary bypass grafts, the risks and benefits of both reoperation and angioplasty, as well as a structure within which to integrate these data. This report reviews the literature and employs formal decision analysis to develop a strategy for management of recurrent angina. Our analysis supports the strategy that patients experiencing recurrent angina within 3 years after surgery should undergo prompt angiographic re-evaluation and angioplasty if anatomically suitable. Symptoms beginning more than 6 years after surgery should be managed medically, reserving surgery for refractory symptoms.

Angina Pectoris↗

PubMed2006

Rational design of aziridine-containing cysteine protease inhibitors with improved potency: studies on inhibition mechanism.

To enable a rational design of improved cysteine protease inhibitors, the present work investigates trends in the inhibition potency of aziridine derivatives with a substituted nitrogen center. To predict the influence of electron-withdrawing substituents, quantum chemical computations of the ring opening of N-formylated, N-methylated, and N-unsubstituted aziridines with thiolate were performed. They revealed that the N-formyl group leads to a strong decrease of the reaction barrier and a considerable increase in exothermicity due to stabilization of the transition state. In contrast, a nucleophilic attack at the carbonyl carbon atom is characterized by very low reaction barriers, suggesting a reversible reaction, thus providing the theoretical background for the reversible inhibition of cysteine proteases by peptidyl aldehydes. Reactions of aziridine building blocks (diethyl aziridine-2,3-dicarboxylate 1, diethyl 1-formyl aziridine-2,3-dicarboxylate 2) with a model thiolate in aqueous solution which were followed by NMR spectroscopy and mass spectrometry, showed the N-formylated compound 2 to readily undergo a ring-opening reaction. In contrast, the reaction of 1 with the thiolate is much slower. Enzyme assays with the cysteine protease cathepsin L showed 2 to be a 5000-fold better enzyme inhibitor than 1. Dialysis assays clearly proved irreversible inhibition. These experiments, together with the results obtained with the model thiolate, indicate that the main inhibition mechanism of the N-formylated aziridine 2 is the ring-opening reaction rather than the reversible attack of the active site cysteine residue at the carbonyl carbon atom.

Aziridines↗