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PubMed2000

Molecular modeling and computer aided drug design. Examples of their applications in medicinal chemistry.

The development of new drugs with potential therapeutic applications is one of the most complex and difficult process in the pharmaceutical industry. Millions of dollars and man-hours are devoted to the discovery of new therapeutical agents. As, the activity of a drug is the result of a multitude of factors such as bioavailability, toxicity and metabolism, rational drug design has been utopias for centuries. Very recently, impressive technological advances in areas such as structural characterization of biomacromolecules, computer sciences and molecular biology have made rational drug design feasible. The aim of this review is to give an outline of studies in the field of medicinal chemistry in which molecular modeling has helped in the discovery process of new drugs. The emphasis will be on lead generation and optimization.

Computer-Aided Design↗
PubMed1994

Recent advances in drug design methods: where will they lead?

Drug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so-called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has no general analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non-peptide scaffolds.

Drug Design↗
PubMed2000

Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase.

The generation of anti-HIV agents using structure-based drug design methods has yielded a number of promising non-nucleoside inhibitors (NNIs) of HIV reverse transcriptase (RT). Recent successes in identifying potent NNIs are reviewed with an emphasis on the recent trend of utilizing a computer model of HIV RT to identify space in the NNI binding pocket that can be exploited by carefully chosen functional groups predicted to interact favorably with binding pocket residues. The NNI binding pocket model was used to design potent NNIs against both wild-type RT and drug-resistant RT mutants. Molecular modeling and score functions were used to analyze how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up, and how these changes could affect inhibitor binding. Modeling studies revealed that for an NNI of HIV RT to be active against RT mutants such as the especially problematic Y181C RT mutant, the following features are required: (a) the inhibitor should be highly potent against wild-type RT and therefore capable of tolerating a considerable activity loss against RT mutants (i.e. a picomolar-level inhibitor against wild-type RT may still be effective against RT mutants at nanomolar concentrations), (b) the inhibitor should maximize the occupancy in the Wing 2 region of the NNI binding site of RT, and (c) the inhibitor should contain functional groups that provide favorable chemical interactions with Wing 2 residues of wild-type as well as mutant RT. Our rationally designed NNI compounds HI-236, HI-240, HI-244, HI-253, HI-443, and HI-445 combine these three features and outperform other anti-HIV agents examined.

Amino Acid Substitution↗
PubMed2001

Stability study of the designer drugs "MDA, MDMA and MDEA" in water, serum, whole blood, and urine under various storage temperatures.

A controlled study was undertaken to determine the stability of the designer drugs MDA, MDMA and MDEA in pooled serum, whole blood, water and urine samples over a period of 21 weeks. The concentrations of the individual designer drugs in the various matrices were monitored over time, in the dark at various temperatures (-20, 4 or 20 degrees C), for a low (+/- 6 ng/ml for water, serum and whole blood and +/- 150 ng/ml for urine) and a high concentration level (+/- 550 ng/ml for water, serum and whole blood and +/- 2500 ng/ml for urine). Compound concentrations were measured using a validated HPLC assay with fluorescence detection. Our study demonstrated no significant loss of the designer drugs in water and urine at any of the investigated temperatures for 21 weeks. The same results were observed in serum for up to 17 weeks, and up to 5 weeks in whole blood. After that time, the compounds could no longer be analyzed due to matrix degradation, especially in the low concentration samples that were stored at room temperature. This study demonstrates that the designer drugs, MDA, MDMA and MDEA are stable when stored at -20 degrees C for 21 weeks, even in haemolysed whole blood.

3,4-Methylenedioxyamphetamine↗
PubMed2003

Utilising structural knowledge in drug design strategies: applications using Relibase.

The concept of structure-based drug design is based upon an in-depth understanding of the principles of molecular recognition. Despite our lack of a thorough comprehension of these principles, the wealth of protein structures available opens up unprecedented possibilities for new insights from the analysis of these data. Unravelling universal rules of molecular recognition is certainly one of the most appealing goals. But our knowledge is enhanced also when studying the specific determinants that characterise single targets or target families only, and the factors governing and discriminating their recognition properties.Here, we illustrate how the structure-based design process can benefit from the consequent incorporation of database query tools. We discuss representative examples to address issues such as protein flexibility, water molecules in binding pockets, and ligand specificity as some of the most critical aspects of drug design. All studies are carried out using our database system Relibase. We also show the application of Relibase in searching for preferred geometrical patterns between interacting molecular fragments.

Animals↗
PubMed2001

Retrometabolic drug design--novel aspects, future directions.

A brief overview of the general, retrometabolic drug design principles, including soft drug and chemical delivery system design, is presented. Selected recent developments within these fields are also summarized, including results related to the design of soft bufuralol and amiodarone analogues, to the airway activity of loteprednol etabonate, a soft corticosteroid, and to the brain targeted delivery of some neuropeptides.

Animals↗
PubMed1994

Computational molecular modeling in peptide drug design.

The review concentrates on practical applications of computer molecular modeling in peptide drug design. The examples of the predictions (successful or not) made by computational modeling before synthesis of peptide analogs, not the explanations provided after synthesis and biological testing of peptides, are discussed. The review spans over 20 years of predictions made by computer molecular modeling for bradykinin, angiotensin, thyrotropin-releasing factor, tuftsin, substance P, CCK-related peptides, luliberin, alpha-melanotropin and opioid peptides. The described examples are discussed in terms of finding the optimal way to use computer modeling for peptide design. The step-by-step 'technology' of peptide design is outlined in detail.

Amino Acid Sequence↗
PubMed2004

Identification of human cytochrome P450 2D6 as major enzyme involved in the O-demethylation of the designer drug p-methoxymethamphetamine.

p-Methoxymethamphetamine (PMMA) is a new designer drug, listed in many countries as a controlled substance. Several fatalities have been attributed to the abuse of this designer drug. Previous in vivo studies using Wistar rats had shown that PMMA was metabolized mainly by O-demethylation. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of PMMA to p-hydroxymethamphetamine. Baculovirus-infected insect cell microsomes, pooled human liver microsomes (pHLMs), and CYP2D6 poor-metabolizer genotype human liver microsomes (PM HLMs) were used for this purpose. Only CYP2D6 catalyzed O-demethylation. The apparent K(m) and V(max) values in baculovirus-infected insect cell microsomes were 4.6 +/- 1.0 microM and 92.0 +/- 3.7 pmol/min/pmol P450, respectively, and 42.0 +/- 4.0 microM and 412.5 +/- 10.8 pmol/min/mg protein in pHLMs. Inhibition studies with 1 microM quinidine showed significant inhibition of the metabolite formation (67.2 +/- 0.6%; p < 0.0001), and comparison of the metabolite formation between pHLMs and PM HLMs revealed significantly lower metabolite formation in the incubations with PM HLMs (87.3 +/- 1.1%; p < 0.0001). According to these studies, CYP2D6 is the major P450 involved in O-demethylation of PMMA.

Amphetamines↗
PubMed2005

Isomeric fluoro-methoxy-phenylalkylamines: a new series of controlled-substance analogues (designer drugs).

An impressively large number of clandestinely produced controlled-substance analogues (designer drugs) of amphetamine with high structural variety have been encountered in forensic samples in recent years. The continuous designer drug exploration and their widespread consumption results in an increasing number of reports regarding abuse and intoxication. This study presents the analytical properties of a series of new fluoro-methoxy-substituted controlled-substance analogues of amphetamine. Three ring positional isomeric fluoroamphetamines, two isomeric fluoromethoxyamphetamines, two N-alkyl 4-fluoroamphetamines, and one 4-fluorophenylbutan-2-amine were identified and differentiated by gas chromatography-mass spectrometry (GC-MS), 1H- and 13C-nuclear magnetic resonance (NMR), and gas chromatography-infrared spectroscopy (GC-IR). The regioisomeric 2-, 3-, and 4-fluoroamphetamines and the regioisomeric fluoro-methoxyamphetamines show virtually identical mass spectra so that this method is insufficient to discriminate between these closely related compounds. The mass spectra of the acetylated compounds allowed a differentiation of the 4-fluoroamphetamine from its regioisomeric 2- and 3-fluoroamphetamines. The gas chromatographic properties of the three regioisomeric fluoroamphetamines and their acetylated and trifluoroacetylated derivatives are also so similar that a complete separation of these compounds could not be achieved under GC-MS conditions. The two isomeric compounds 5-fluoro-2-methoxyamphetamine and 3-fluoro-4-methoxyamphetamine on the other hand showed significant different gas chromatographic retention times so that a separation was uncomplicated. The trifluoroacetylation of these compounds proved to be an effective method for their mass spectral differentiation. Gas chromatography-infrared spectroscopy and 1H- and 13C-nuclear magnetic resonance allowed an unequivocal differentiation of all studied regioisomeric fluoroamphetamines and fluoro-methoxyamphetamines.

Amphetamines↗
PubMed2005

Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems.

Despite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tear-flow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifically developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specific effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifically designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on beta-adrenergic agonists and anti-inflammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specific drug design approaches.

Adrenal Cortex Hormones↗
PubMed1994

[Development of quantitative structure-activity relationships and computer-aided drug design].

Recent development of quantitative structure-activity relationships (QSARs) and computer-aided drug design contributed by the author and his coworkers was briefly reviewed. Fuzzy adaptive least-squares (FALS), a pattern recognition method for analysing structure-activity rating data to generate QSAR models was developed. A novel feature of FALS is that the degree to which each sample belongs to its activity class is given by a fuzzy membership function. Using FALS, non-congeneric QSAR analyses of carcinogenicity, mutagenicity, and six kinds of pharmacokinetic properties of miscellaneous organic chemicals were performed to construct predictive models for drug design. In these QSAR analyses, the values of log P (partition coefficient in octanol/water) calculated by the simple method of Moriguchi et al. were used as the descriptor for hydrophobicity. The method of Moriguchi et al. is not only simple and convenient but also reliable in the application to 22 drugs selected by Rekker et al. compared to the Rekker method and the Hansch-Leo method. Lastly, a heulistic search method for active conformers using molecular mechanical conformational analysis and principal component analysis was proposed.

Animals↗
PubMed2000

Confirmation testing of amphetamines and designer drugs in human urine by capillary electrophoresis-ion trap mass spectrometry.

Monitoring of amphetamines and designer drugs in human urine is a timely topic in clinical toxicology, surveillance of drug substitution, forensic science, drug testing at the workplace, and doping control. Confirmation testing of urinary amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and 3,4-methylenedioxyamphetamine (MDA) by capillary electrophoresis (CE) combined with atmospheric pressure electrospray ionization and ion trap mass spectrometry (MS) is described. Using an aqueous pH 4.6 buffer composed of ammonium acetate/acetic acid, CE-MS and CE-MS2 provided data that permitted the unambiguous confirmation of these drugs in external quality control urines. Furthermore, other drugs of abuse present in alkaline urinary extracts, including methadone and morphine, could also be monitored. The data presented illustrate that the sensitivity achieved with the benchtop MS is comparable to that observed by CE with UV absorption detection. CE-MS2 is further shown to be capable of identifying comigrating compounds, including the comigration of amphetamine with nicotine.

Amphetamines↗
PubMed2000

Recent advances in structure-based rational drug design.

Two approaches to structure-based drug design, that is, the docking of known compounds into a target protein and molecular assembly in situ, are seen to be merging technologies. The need for structural information about drug-protein complexes is now fundamental for drug discovery.

Animals↗
PubMed2006

Sensor/effector drug design with potential relevance to cancer.

Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their 'healthy' counterparts. Some tumors, such as solid lung carcinoma, are hypoxic, and its cells are therefore more reducing than normal, while others, such as the ones of breast and prostate cancer, proliferate under oxidative stress (OS). These biochemical differences between normal and tumor tissue are significant, and can be used to design effective, yet selective redox drugs. The resulting drug design can follow different avenues. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro-drug molecules inside cancer cells by a reductive step, often followed by further chemical transformations, such as hydrolysis. Related anti-cancer compounds, such as varacin, employ an intricate combination of reduction and oxidation processes to develop their therapeutic potential inside cells. Another, just emerging approach considers the use of pro-oxidants and catalysts, taking advantage of the inherent efficiency and selectivity associated with OS-induced cell death. Even more complex tactics, such as chelator-assisted photodynamic therapy, exploit the intracellular metal homeostasis to target cancer cells. Together, all of these avenues try to endow molecules with a combination of sensor and effector properties, which might allow them to single out and selectively kill cancer cells without the need for cell-selective drug delivery systems. In the long term, such agents could be associated with high efficiency, good selectivity and dramatically reduced drug side effects.

Animals↗
PubMed2004

Development of KiBank, a database supporting structure-based drug design.

KiBank is a database of inhibition constant (Ki) values with 3D structures of target proteins and chemicals. Ki values were accumulated from peer-reviewed literature searched via PubMed. The 3D structure files of target proteins were originally from Protein Data Bank (PDB), while the 2D structure files of the chemicals were collected together with the Ki values and then converted into 3D ones. In KiBank, the chemical and protein 3D structures with hydrogen atoms were optimized by energy minimization and stored in MDL MOL and PDB format, respectively. KiBank is designed to support structure-based drug design. It provides structure files of proteins and chemicals ready for use in virtual screening through automated docking methods, while the Ki values can be applied for tests of docking/scoring combinations, program parameter settings, and calibration of empirical scoring functions. Additionally, the chemical structures and corresponding Ki values in KiBank are useful for lead optimization based on quantitative structure-activity relationship (QSAR) techniques. KiBank is updated on a daily basis and is freely available at . As of August 2004, KiBank contains 8000 Ki values, over 6000 chemicals and 166 proteins covering the subtypes of receptors and enzymes.

Binding Sites↗
PubMed2004

Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.

HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.

Binding Sites↗
PubMed2006

The cyclotides and related macrocyclic peptides as scaffolds in drug design.

The applicability of linear peptides as drugs is potentially limited by their susceptibility to proteolytic cleavage and poor bioavailability. Cyclotides are macrocyclic cystine-knotted mini-proteins that have a broad range of bioactivities and are exceptionally stable, being resistant to chemical, thermal and enzymatic degradation. The general limitations of peptides as drugs can potentially be overcome by using the cyclotide framework as a scaffold onto which new activities may be engineered. The potential use of cyclotides and related peptide scaffolds for drug design is evaluated herein, with reference to increasing knowledge of the structures and sequence diversity of natural cyclotides and the emergence of new approaches in protein engineering.

Amino Acid Sequence↗