N-Cycloalkanoyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists

A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.     

A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin

Using the X-ray crystal structure of the human topoisomerase I (TOP1)-DNA cleavable complex, we have developed a general model for the ternary drug-DNA-TOP1 cleavable complex formed with camptothecin (CPT) and its analogues. This model has the drug intercalated between the -1 and +1 base pairs, with the E-ring pointing into the minor groove and the A-ring directed toward the major groove. The ternary complex is stabilized by an array of hydrogen bonding and hydrophobic interactions between the drug and both the enzyme and the DNA. Significantly, the proposed model is consistent with the current body of experimental mutation, cross-linking, and structure-activity data. In addition, the model reveals potential sites of interaction that can provide a rational basis for the design of next generation compounds as well as for de novo drug design.     

Evaluation of NTF1836 as an inhibitor of the mycothiol biosynthetic enzyme MshC in growing and non-replicating Mycobacterium tuberculosis

The mycothiol biosynthesis enzyme MshC catalyzes the ligation of cysteine with the pseudodisaccharide GlcN-Ins and has been identified as an essential enzyme in Mycobacterium tuberculosis. We now report on the development of NTF1836 as a micromolar inhibitor of MshC. Using commercial libraries, we conducted preliminary structure-activity relationship (SAR) studies on NTF1836. Based on this data, NTF1836 and five structurally related compounds showed similar activity towards clinical strains of M. tuberculosis. A gram scale synthesis was developed to provide ample material for biological studies. Using this material, we determined that inhibition of M. tuberculosis growth by NTF1836 was accompanied by a fall in mycothiol and an increase in GlcN-Ins consistent with the targeting of MshC. We also determined that NTF1836 kills non-replicating M. tuberculosis in the carbon starvation model of latency.     

Synthesis and cytotoxic evaluation of a series of resveratrol derivatives

A total of 17 resveratrol (=(E)-5-[2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol) derivatives were synthesized from resveratrol (RES) through a facile approach. Among them, 13 compounds, 2 and 6-17, were reported for the first time, while 1 and 3-5 had already been reported several years ago. The cytotoxic activities of these compounds were evaluated against human nasopharyngeal epidermoid tumor cell line KB, and compounds 1 and 8-11 showed strong anticancer activities in vitro, comparable with that of 5-fluorouracil, an anticancer drug. On the basis of the experimental data obtained, structure-activity relationships are discussed.     

Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function

We have employed a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the biochemical activity for inhibitors of T. cruzi dihydrofolate reductase-thymidylate synthase (DHFR-TS). Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state (DHFR domain) were used to validate and refine docking poses of ligands that constitute likely active conformations. Structural information from these complexes formed the basis for the structure-based alignment used as input for the QSAR study. Contrary to indirect ligand-based approaches the strategy described here employs a direct receptor-based approach. The goal is to generate a library of selective lead inhibitors for further development as antiparasitic agents. 3D-QSAR models were obtained for T. cruzi DHFR-TS (30 inhibitors in learning set) and human DHFR (36 inhibitors in learning set) that show a very good agreement between experimental and predicted enzyme inhibition data. For crossvalidation of the QSAR model(s), we have used the 10% leave-one-out method. The derived 3D-QSAR models were tested against a few selected compounds (a small test set of six inhibitors for each enzyme) with known activity, which were not part of the learning set, and the quality of prediction of the initial 3D-QSAR models demonstrated that such studies are feasible. Further refinement of the models through integration of additional activity data and optimization of reliable docking poses is expected to lead to an improved predictive ability.     

Design, synthesis, biochemical studies, cellular characterization, and structure-based computational studies of small molecules targeting the urokinase receptor

The urokinase receptor (uPAR) serves as a docking site to the serine protease urokinase-type plasminogen activator (uPA) to promote extracellular matrix (ECM) degradation and tumor invasion and metastasis. Previously, we had reported a small molecule inhibitor of the uPAR·uPA interaction that emerged from structure-based virtual screening. Here, we measure the affinity of a large number of derivatives from commercial sources. Synthesis of additional compounds was carried out to probe the role of various groups on the parent compound. Extensive structure-based computational studies suggested a binding mode for these compounds that led to a structure-activity relationship study. Cellular studies in non-small cell lung cancer (NSCLC) cell lines that include A549, H460 and H1299 showed that compounds blocked invasion, migration and adhesion. The effects on invasion of active compounds were consistent with their inhibition of uPA and MMP proteolytic activity. These compounds showed weak cytotoxicity consistent with the confined role of uPAR to metastasis.     

Re-engineering aryl methylcarbamates to confer high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase

To identify potential human-safe insecticides against the malaria mosquito we undertook an investigation of the structure-activity relationship of aryl methylcarbamates inhibitors of acetylcholinesterase (AChE). Compounds bearing a β-branched 2-alkoxy or 2-thioalkyl group were found to possess good selectivity for inhibition of Anopheles gambiae AChE over human AChE; up to 530-fold selectivity was achieved with carbamate 11d. A 3D QSAR model is presented that is reasonably consistent with log inhibition selectivity of 34 carbamates. Toxicity of these compounds to live Anopheles gambiae was demonstrated using both tarsal contact (filter paper) and topical application protocols.     

Molecular modeling in the design of phospholipase A2 inhibitors

The X-ray structures of pancreatic bovine and porcine phospholipases A2 have been used along with interactive computer graphics to design conformationally rigid, novel compounds (1-meta-hydroxybenzyl-2-substituted acenaphthenes) directed at the active sites of these enzymes. In vitro testing confirmed that the designed compounds are potent inhibitors of the porcine pancreatic phospholipase A2 and exhibit both stereoselectivity and structure-activity relationships that are consistent with the proposed mode of binding. These compounds take advantage of a hydrophobic "slot" positioned between residues Leu-2 and Tyr-69 while positioning hydrogen-bonding functionality directed at the nd1-N of His-48. Experimental evidence shows a regioselective preference for this H-bond acceptor. A second part of the strategy used a tethered amine to displace the essential calcium providing a bisubstrate analog.     

In silico prediction of novel phosphodiesterase type-5 inhibitors derived from Sildenafil, Vardenafil and Tadalafil

A series of drug-like compounds derived from Sildenafil, Vardenafil and Tadalafil analogues were modelled through the MIA-QSAR (multivariate image analysis applied to quantitative structure-activity relationships) ligand-based approach. A highly predictive model was achieved and novel compounds, miscellany of substructures of these three representative phosphodiesterase type-5 (PDE-5) inhibitors were predicted using the calibration parameters obtained through partial least squares (PLS) regression. The high bioactivities of eight promising compounds were corroborated by docking evaluation. Calculated ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) profiles for such compounds suggest advantages of some of them over the currently available, most common drugs used for the treatment of erectile dysfunction.     

Modeling and docking the endothelin G-protein-coupled receptor

A model of the endothelin G-protein-coupled receptor (ET(A)) has been constructed using a segmented approach. The model was produced using a bovine rhodopsin model as a template for the seven transmembrane alpha-helices. The three cytoplasmic loop regions and the C-terminal region were modeled on NMR structures of corresponding segments from bovine rhodopsin. The three extracellular loops were modeled on homologous loop regions in other proteins of known structure. The N-terminal region was modeled as a three-helix domain based on its homology with a hydrolase protein. To test the model, the FTDOCK algorithm was used to predict the ligand-binding site for the crystal structure of human endothelin. The site of docking is consistent with mutational and biochemical data. The principal sites of interaction in the endothelin ligand all lie on one face of a helix that has been implicated by structure-activity relationship studies as being essential for binding. As further support for the model, attempts to dock bigET, an inactive precursor to endothelin that does not bind to the receptor, found no sites for tight binding. The model of the receptor-ligand complex produced forms a basis for rational drug design of agonists and antagonists for this G-protein-coupled receptor.     

Central nervous system drug design

A model which suggests that there is a common structural basis for the action of many different classes of CNS drugs is described. It is shown that this general model is consistent with specific models for opioid analgesic and antidepressant activity. The significance of these models is not only that they define specific spatial relationships between the structural requirements in different CNS drug classes, but also that they allow the formulation of three very simple drug design techniques which will be referred to as pruning, splicing and grafting. When combined with available structure-activity information, these techniques may provide a rational approach to the design of drugs with specified CNS activity.     

Quantitative structure-activity relationship studies on benzodiazepine receptor binding: recognition of active sites in receptor and modelling of interaction.

A quantitative structure-activity relationship study was carried out for the binding of a series of 'classical' benzodiazepines (BZs) and some beta-carbolines with BZ receptors to investigate the active sites in the latter and the nature of the binding of compounds with them. Using the Hansch approach, an attempt was made to correlate binding affinities of compounds with various physico-chemical and electronic properties of substituents. The correlations obtained showed the main roles were played by the hydrophobic constant pi and the Hammett constant sigma (an electronic parameter) of various substituents. This led to the suggestion that BZ receptors have many additional hydrophobic, hydrogen bonding and polar sites other than those suggested by Hollinshead et al. (1990). From the present study, the Hollinshead model of interaction was found to be inadequate to account fully for the binding of all types of compounds.     

Respiratory syncytial virus fusion inhibitors. Part 5: Optimization of benzimidazole substitution patterns towards derivatives with improved activity

Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure-activity relationships for this compound series, substitution of the benzimidazole ring was examined with a view to establishing additional productive interactions between the inhibitor and functionality present in the proposed binding pocket. Amongst the compounds synthesized, the 5-aminomethyl analogue 10aa demonstrated potent antiviral activity towards wild-type RSV and retained excellent inhibitory activity towards a virus that had been developed to express resistance to BMS-433771 (3), data consistent with an additional productive interaction between the inhibitor and the fusion protein target.     

QSAR study on para-substituted aromatic sulfonamides as carbonic anhydrase II inhibitors using topological information indices

A linear quantitative structure-activity relationship has been developed for a series of para-substituted aromatic sulfonamides by using topological index methodologies. The compounds were studied for their carbonic anhydrase II (CAII) inhibitory activity. A large series of topological indices were calculated and the stepwise regression method was used to derive the most significant model. Very good results were obtained using multi-parametric regressions and showed that the information approach used in the present work is quite useful for modeling carbonic anhydrase inhibition.