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PubMed2001

Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).

PURPOSE: The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates. METHODS: The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC-BP-calcium complex. RESULTS: Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = -0.868 approximately -0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC-BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC-BP could precipitate with calcium in the plasma circulation. CONCLUSIONS: Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate-calcium complex.

Algorithms↗
PubMed2003

A peptide mimetic of an anti-CD4 monoclonal antibody by rational design.

The development of rational methods to design 'continuous' sequence mimetics of discontinuous regions of protein sequence has, to now, been only marginally successful. This has been largely due to the difficulty of constraining the recognition elements of a mimetic structure to the relative conformational and spatial orientations present in the parent molecule. Using peptide mapping to determine 'active' antigen recognition residues, molecular modeling, and a molecular dynamics trajectory analysis, we have developed a peptide mimic of an anti-CD4 antibody, containing antigen contact residues from multiple CDRs. The design described is a 27-residue peptide formed by juxtaposition of residues from 5 CDR regions. It displays an affinity for the antigen (CD4) of 0.9nM, compared to 2nM for the parent antibody ST40. Nevertheless, the mimetic shows low biological activity in an anti-retroviral assay.

Amino Acid Sequence↗
PubMed1998

Random or rational design? Evaluation of diverse compound subsets from chemical structure databases.

The performance of rational design to maximize the structural diversity of databases for lead finding and lead refinement was investigated. Rational methods such as maximum dissimilarity methods or hierarchical cluster analysis for designing compound subsets were compared to a random approach to study their efficiency for an enhancement of the diversity of three different databases. All investigations were done based on 2D fingerprints as a validated molecular descriptor. To compare the performance of the rational selection methods to a random approach, we additionally used probability calculations. When using maximum dissimilarity-based selections, a single compound can be a member of different neighborhoods as defined by the similarity threshold value, while in hierarchical clustering each compound is assigned to only a single cluster. Therefore the relationship between the similarity threshold of the maximum diversity selection method and a 2D similarity search threshold was studied. In contrast to hierarchical clustering analysis, maximum dissimilarity selections allow to use a similarity threshold for adding a new compound to an already selected compound list. Reasonable values for this similarity threshold are presented here. More diverse subsets were designed using maximum dissimilarity selections, which cover more biological classes than using random selections. An optimally diverse subset without redundant structures containing only 38% of one original dataset was generated, where no structure is more similar than 0.85 to its nearest neighbor, but all biological classes were represented. When it is acceptable to cover only 90% of all biological targets, 3.5-3.7 times more compounds need to be selected using a random approach than in a rational design approach. Such coverage rate shows the highest efficiency of design techniques compared to a random approach. In those subsets no compound is closer than 0.70 to its nearest neighbor. Furthermore a comparative molecular field analysis (CoMFA) is used to evaluate designed and randomly chosen subsets for a database consisting of inhibitors of the angiotensin-converting enzyme. It was shown that designed subsets using maximum dissimilarity methods lead to more stable quantitative structure-activity relationship (QSAR) models with higher predictive power compared to randomly chosen compounds. This predictive power is especially high when there is no compound in the test dataset with a similarity coefficient less than 0.7 to its nearest neighbor in the training set.

Databases as Topic↗
PubMed2005

Evaluation of fluorenhymustine as a rationally designed novel anticancer agent.

AIM: To develop a rationally designed new nitrogen mustard namely Fluorenhymustine (compound 2), where N,N'-bis(2chloro-ethyl)amino group, the established anticancer functionality, is attached to the 2-ethyl fluorenone hydantoin moiety. MATERIALS AND METHODS: Starting from fluorenone hydantoin, a 3-step synthetic procedure was followed to obtain the title compound. 4-(4-Nitrobenzyl)pyridine was used to assess its chemical alkylating activity. Murine tumors (Ehrlich ascites carcinoma (EAC) and Sarcoma-180 (S-180)) were used to assess its in vivo activity. Its cytotoxicity was determined in vitro in MCF-7 human breast tumor cell line, toxicity - in vivo in normal and EAC bearing mice. 3H-Thymidine and 3H-Uridine were employed to study its inhibitory effect on DNA and RNA synthesis respectively in S-180 tumor cells in vitro. RESULTS: Alkylating activity of fluorenmustine exceeded that of N-di(2-chloroethyl)amine used as a standard alkylating compound. It has displayed an excellent and reproducible antitumor activity in vivo against EAC and S-180 comparable to that of 5-fluorouracil judging by the increase in median survival times of treated animals. It also significantly increased the life span of mice bearing advanced tumors for 6 days before the drug challenge. However in vitro screening in MCF-7 did not reveal any significant cytotoxicity. The compound did not adversely affect hematopoiesis at its optimum dose. Drug-induced hepatotoxicity and nephrotoxicity were also not detected. It inhibited the synthesis of DNA and RNA in S-180 tumor cells at 8 microM concentration. CONCLUSION: Results indicated promising chemotherapeutic potential of Fluorenhymustine.

Animals↗
PubMed1999

Rational design of a GCN4-derived mimetic of interleukin-4.

In this work we describe the rational design of two helix coiled coil peptide mimetics of interleukin-4 (IL-4) which are able to recognize and bind its high affinity receptor (IL-4R alpha). We have used the leucine-zipper domain of the yeast transcription factor GCN4 as a scaffold into which the putative binding epitope of IL-4 for IL-4R alpha was transferred in a stepwise manner, using computer-aided molecular modeling. The resulting molecules bind IL-4R alpha with affinities ranging from 2 mM to 5 microM, depending on the fraction of the IL-4 binding site incorporated and on their stability. To our knowledge this is the first time a molecule capable of binding a cytokine receptor has been successfully designed in a rational manner.

Amino Acid Sequence↗
PubMed2003

Disulfide by Design: a computational method for the rational design of disulfide bonds in proteins.

SUMMARY: Disulfide by Design is a program for the design of novel disulfide bonds in proteins. Protein structure files in PDB format are analyzed to identify residue pairs that are likely to form a disulfide bond if the respective amino acids are mutated to cysteines. The output displays residue pairs having the appropriate geometric characteristics for disulfide formation and provides automated generation of modified PDB files including modeled disulfides. Validation demonstrates a high level of accuracy for the algorithm. AVAILABILITY: http://www.ehscenter.org/dbd/ SUPPLEMENTARY INFORMATION: http://www.ehscenter.org/dbd/

Algorithms↗
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↗
PubMed2002

Rational design and development of RDP58.

We used a novel rational design approach in the development of novel immunomodulatory peptides, in particular RDP58, with at least two primary biological activities, inhibition of TNF production and upregulation of heme oxygenase-1 (HO-1) activity. The design strategy used a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories to identify potential drug candidates. The process was initiated using a panel of 19 lead molecules derived from a functionally-important region of HLA I, on the premise that the peptides might modulate immune responses by blocking HLA/T lymphocyte interactions. Each of these 19 peptides was tested in vivo for potential cardiac allograft protection in a mouse model. Outcome of graft survival was the primary data available to describe nine of the peptides as active and ten as inactive. A virtual combinatorial library of 279,936 peptides was then generated, based on physical properties associated with efficacy in the original learning set of 19 peptides--in particular, the distribution of lipophilic residues. The library was screened using descriptors that fell into 2 categories: static (physico-chemical) and dynamic (conformational). The screenings identified 5 peptides with theoretic potential efficacy. These were synthesized and tested for activity in vitro and in vivo. Besides prolonging graft survival in rodents, RDP58 was found to inhibit TNF and increase HO-1 activity; these biological activities were tested exhaustively in various in vivo disease models. RDP58 demonstrated convincing potential to alleviate disease symptoms in many of the experimental diseases.

Animals↗
PubMed2001

Microbial pathway engineering for industrial processes: evolution, combinatorial biosynthesis and rational design.

Microbial pathway engineering has made significant progress in multiple areas. Many examples of successful pathway engineering for specialty and fine chemicals have been reported in the past two years. Novel carotenoids and polyketides have been synthesized using molecular evolution and combinatorial strategies. In addition, rational design approaches based on metabolic control have been reported to increase metabolic flux to specific products. Experimental and computational tools have been developed to aid in design, reconstruction and analysis of non-native pathways. It is expected that a hybrid of evolutionary, combinatorial and rational design approaches will yield significant advances in the near future.

Carotenoids↗
PubMed2004

Strategies for fed-batch cultivation of t-PA producing CHO cells: substitution of glucose and glutamine and rational design of culture medium.

A strategy for fed-batch cultivation of t-PA producing recombinant CHO cells is presented, based on the substitution of glucose and glutamine for slowly metabolized nutrients and in a rational design of the medium. Media for the batch and fed stages were based on the cell specific amino acid requirements, which allowed a more accurate determination of the initiation of the fed stage and the frequency of nutrient addition from then on. Salt concentration was also reduced in both media to avoid an increase in osmolality. As a consequence of this rational design, most amino acid did not accumulate significantly during the fed stage, as usually occurs when their supply is not based on cell requirements; also, lower amounts of by-products were obtained when osmolality level was kept low, that altogether increased viability, longevity and t-PA production when compared with a reference batch culture. Alternating glucose and galactose during the fed stage, allowed lactate detoxification of the cells through their own metabolism. This allowed an increase in cell growth and cell viability with respect to a fed-batch culture in which only glucose was used in the fed stage.

Animals↗
PubMedDate not supplied

Rational combinatorial library design. 2. Rational design of targeted combinatorial peptide libraries using chemical similarity probe and the inverse QSAR approaches.

We have developed a novel strategy for rational design of targeted peptide libraries. The goal of this method is to select a subset of natural amino acids that are most likely to be present in active peptides for the synthesis of library. Two different protocols are employed where chemical structures of peptides are described either by topological indices or by a combination of physicochemical descriptors for individual amino acids. The selection of a peptide as a candidate for the targeted library is based either on its chemical similarity to a biologically active probe or on its biological activity predicted from a preconstructed quantitative structure-activity (QSAR) equation. The optimization of the library is achieved by means of genetic algorithms (GA). This method was tested by rational design of the library with bradykinin-potentiating activity. Twenty-eight bradykinin-potentiating pentapeptides were used as a training set for the development of a QSAR equation, and, alternatively, two active pentapeptides, VEWAK and VKWAP, were used as probe molecules. In each case, the frequency distribution of amino acids in the top 100 peptides suggested by the method resembles the frequency distribution of amino acids found in the active peptides. The results obtained after GA optimization also compared favorably with those obtained by the exhaustive analysis of all possible 3.2 million pentapeptides.

Algorithms↗
PubMed1993

Synthesis, structure and activity of artificial, rationally designed catalytic polypeptides.

Biological macromolecules with catalytic activity can be created artificially using two approaches. The first exploits a system that selects a few catalytically active biomolecules from a large pool of randomly generated (and largely inactive) molecules. Catalytic antibodies and many catalytic RNA molecules are obtained in this way. The second involves rational design of a biomolecule that folds in solution to present to the substrate an array of catalytic functional groups. Here we report the synthesis of rationally designed polypeptides that catalyse the decarboxylation of oxaloacetate via an imine intermediate. We determine the secondary structures of the polypeptides by two-dimensional NMR spectroscopy. We are able to trap and identify intermediates in the catalytic cycle, and to explore the kinetics in detail. The formation of the imine by our artificial oxaloacetate decarboxylases is three to four orders of magnitude faster than can be achieved with simple amine catalysts: this performance rivals that of typical catalytic antibodies.

Amines↗
PubMed2001

Rational design of fluorescein-based fluorescence probes. Mechanism-based design of a maximum fluorescence probe for singlet oxygen.

Fluorescein is one of the best available fluorophores for biological applications, but the factors that control its fluorescence properties are not fully established. Thus, we initiated a study aimed at providing a strategy for rational design of functional fluorescence probes bearing fluorescein structure. We have synthesized various kinds of fluorescein derivatives and examined the relationship between their fluorescence properties and the highest occupied molecular orbital (HOMO) levels of their benzoic acid moieties obtained by semiempirical PM3 calculations. It was concluded that the fluorescence properties of fluorescein derivatives are controlled by a photoinduced electron transfer (PET) process from the benzoic acid moiety to the xanthene ring and that the threshold of fluorescence OFF/ON switching lies around -8.9 eV for the HOMO level of the benzoic acid moiety. This information provides the basis for a practical strategy for rational design of functional fluorescence probes to detect certain biomolecules. We used this approach to design and synthesize 9-[2-(3-carboxy-9,10-dimethyl)anthryl]-6-hydroxy-3H-xanthen-3-one (DMAX) as a singlet oxygen probe and confirmed that it is the most sensitive probe currently known for (1)O(2). This novel fluorescence probe has a 9,10-dimethylanthracene moiety as an extremely fast chemical trap of (1)O(2). As was expected from PM3 calculations, DMAX scarcely fluoresces, while DMAX endoperoxide (DMAX-EP) is strongly fluorescent. Further, DMAX reacts with (1)O(2) more rapidly, and its sensitivity is 53-fold higher than that of 9-[2-(3-carboxy-9,10-diphenyl)anthryl]-6-hydroxy-3H-xanthen-3-ones (DPAXs), which are a series of fluorescence probes for singlet oxygen that we recently developed. DMAX should be useful as a fluorescence probe for detecting (1)O(2) in a variety of biological systems.

Fluorescein↗
PubMed2006

Rational design of a beta-lactamase inhibitor achieved via stabilization of the trans-enamine intermediate: 1.28 A crystal structure of wt SHV-1 complex with a penam sulfone.

beta-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of beta-lactamases that are capable of hydrolyzing our most potent beta-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the trans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 beta-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A beta-lactamase inhibitors.

Amines↗
PubMed1977

Rational design of arabinosyl nucleosides as antitumor and antiviral agents.

The rational design of antitumor and antiviral agents must ultimately take advantage of biochemical differences between normal host cells and transformed cells. The initial experiments must be performed with subcellular or cellular model systems. For the studies with arabinosyl nucleosides we have chosen those enzyme systems, synthesizing DNA and RNA; being precursor analogues, the different arabinosyl nucleosides have been added in the triphosphate state to the different DNA- and RNA polymerase assays. 1-beta-D-Arabinofuranosylcytosine-5'-triphosphate has been found to inhibit the RNA-dependent DNA polymerases (isolated from oncogenic RNA viruses) 200-fold more sensitively than viral and cellular DNA-dependent DNA polymerases. Recent results, showing that RNA-leukemia-virus-related sequences are present in DNA of some human leukemia patients might support the assumption that the efficacy of this antimetabolite in the treatment of acute leukemia is due to its, at least relative selective inhibitory activity on reverse transcriptase. 9-beta-D-Arabinofuranosyladenine-5'-triphosphate is a strong inhibitor of cellular DNA polymerases with the cytological consequence of an inhibition of cell proliferation. The clinical benefit of the compound in treatment of tumors is dependent on their levels of adenosine deaminase. The triphosphate of this compound is a 100-fold more sensitive inhibitor of the herpesvirus DNA polymerase compared to the cellular replicative DNA polymerase. In addition the analogue, incorporated into herpesvirus DNA, acts as chain terminator. These effects are the biochemical basis for the highly selective antiherpesvirus activity of this antimetabolite. The anomer 9-alpha-D-arabinofuranosyladenine-5'-triphosphate only inhibits cellular replicative DNA polymerase and has no effect on herpesvirus DNA polymerase. Consequently this agent acts only cytostatically and not antivirally. Concerning 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylthymine no pronounced antitumor or antiviral effect is known.

Animals↗
PubMed2001

Rational design of lipid molecular structure: a case study involving the C19:1c10 monoacylglycerol.

The phase properties of lipids have far-reaching consequences in membrane biology. Their influence ranges from domain formation in intact biomembranes to membrane protein reconstitution and crystallization. To exploit phase behavior in the spirit of rational design, it is imperative that the rules relating lipid molecular structure and liquid crystal or mesophase behavior be established. Phase behavior is quantitatively and concisely represented in the form of temperature-composition phase diagrams. A somewhat limited number of phase diagrams exists for the monoacylglycerols. The objective of the current study was to determine the quality of phase behavior prediction for a specific monoacylglycerol based on an analysis of the existing phase diagrams for related chain homologs. To this end, a phase diagram for the monononadecenoin (19:1c10)/water system was predicted in the temperature range from -15 degrees C to 120 degrees C and from 0% to 80% (w/w) water. The prediction was tested by constructing the corresponding phase diagram using low- and wide-angle x-ray diffraction, differential scanning calorimetry, and polarized light microscopy. The results show that the predicted and experimental phase diagrams agree remarkably well. They also highlight the need for additional phase studies of the type described to enlarge the data bank of phase diagrams and to strengthen the foundations of the rational design approach.

Calorimetry, Differential Scanning↗
PubMed1997

The rational design and construction of a cuboidal iron-sulfur protein.

Rational protein design is an emerging approach for testing general theories of protein chemistry through the creation of new structures and functions. Here we present the first successful introduction by rational design of a [Fe4S4] cuboidal cluster into the hydrophobic core of Escherichia coli thioredoxin, a protein normally devoid of metal centers. Cuboidal [Fe4S4] is one of the stable forms of self-assembled iron-sulfur clusters that are thought to represent some of the earliest evolved biological redox centers. [Fe4S4] clusters have been recruited for use in a variety of proteins whose functions are central to many of the major biochemical processes ranging from simple soluble electron-transfer agents, to membrane-bound components of electron-transfer chains, to electron reservoirs in complex metalloenzymes such as nitrogenase. By situating an [Fe4S4] cluster into a protein environment not previously adapted by evolution we can explore the factors by which their activity is modulated by the protein matrix.

Algorithms↗
PubMed2005

Rational design of intercellular adhesion molecule-1 (ICAM-1) variants for antagonizing integrin lymphocyte function-associated antigen-1-dependent adhesion.

The interaction between integrin lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) is critical in immunological and inflammatory reactions but, like other adhesive interactions, is of low affinity. Here, multiple rational design methods were used to engineer ICAM-1 mutants with enhanced affinity for LFA-1. Five amino acid substitutions 1) enhance the hydrophobicity and packing of residues surrounding Glu-34 of ICAM-1, which coordinates to a Mg2+ in the LFA-1 I domain, and 2) alter associations at the edges of the binding interface. The affinity of the most improved ICAM-1 mutant for intermediate- and high-affinity LFA-1 I domains was increased by 19-fold and 22-fold, respectively, relative to wild type. Moreover, potency was similarly enhanced for inhibition of LFA-1-dependent ligand binding and cell adhesion. Thus, rational design can be used to engineer novel adhesion molecules with high monomeric affinity; furthermore, the ICAM-1 mutant holds promise for targeting LFA-1-ICAM-1 interaction for biological studies and therapeutic purposes.

Cell Adhesion↗