Analysis of human carbonic anhydrase II: docking reliability and receptor-based 3D-QSAR study

The ability of Gold software to predict the binding disposition of carbonic anhydrase (CA) inhibitors was evaluated using CA II as a case study. The best procedure was subsequently used for docking almost 300 CA II ligands, and the best poses were used as an alignment tool for the development of a 3D quantitative structure-activity relationship (QSAR) study. Evaluation of the resulting 3D-QSAR model allowed us to indicate the ligand properties and residues important for CA II inhibition. Since CAs are an important target involved in many pathologies such as glaucoma, obesity, and tumors, the results obtained could accurately predict the binding affinity of newly designed CA II inhibitors. Furthermore, it is reasonable that this strategy could be profitably used also for the investigation of other CAs.     

Comparison of ligand-based and receptor-based virtual screening of HIV entry inhibitors for the CXCR4 and CCR5 receptors using 3D ligand shape matching and ligand-receptor docking

HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120 protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 co-receptors. There is currently considerable interest in developing novel ligands that can modulate the conformations of these co-receptors and, hence, ultimately block virus-cell fusion. This article describes a detailed comparison of the performance of receptor-based and ligand-based virtual screening approaches to find CXCR4 and CCR5 antagonists that could potentially serve as HIV entry inhibitors. Because no crystal structures for these proteins are available, homology models of CXCR4 and CCR5 have been built, using bovine rhodopsin as the template. For ligand-based virtual screening, several shape-based and property-based molecular comparison approaches have been compared, using high-affinity ligands as query molecules. These methods were compared by virtually screening a library assembled by us, consisting of 602 known CXCR4 and CCR5 inhibitors and some 4700 similar presumed inactive molecules. For each receptor, the library was queried using known binders, and the enrichment factors and diversity of the resulting virtual hit lists were analyzed. Overall, ligand-based shape-matching searches yielded higher enrichments than receptor-based docking, especially for CXCR4. The results obtained for CCR5 suggest the possibility that different active scaffolds bind in different ways within the CCR5 pocket.     

Ligand-, copper-, and amine-free sonogashira reaction of aryl iodides and bromides with terminal alkynes

Conditions for an efficient ligand-, copper-, and amine-free palladium-catalyzed Sonogashira reaction of aryl iodides and bromides with terminal alkynes have been developed. Critical to the success of this new protocol is the use of tetrabutylammonium acetate as the base. Noteworthy features of this method are room-temperature conditions and the tolerance of a broad range of functional groups in both reaction partners.     

Homology modeling and receptor-based 3D-QSAR study of carbonic anhydrase IX

Carbonic anhydrase (CA) IX is a very interesting subject for study due to its overexpression in cancer and its expression in very few normal tissues. There are not yet experimental 3D structures of the catalytic domain of this isozyme, and only a few computational studies have been reported. A homology model of CA IX was developed, and using Gold software 124 CA IX inhibitors were docked. The best poses of the ligands were then used as an alignment tool for the development of the first reported CA IX 3D-QSAR model. The obtained results confirm the reliability of the constructed CA IX model and the proposed computational strategy for investigating CAs.     

Ligand-protein docking with water molecules

The presence of water molecules plays an important role in the accuracy of ligand-protein docking predictions. Comprehensive docking simulations have been performed on a large set of ligand-protein complexes whose crystal structures contain water molecules in their binding sites. Only those water molecules found in the immediate vicinity of both the ligand and the protein were considered. We have investigated whether prior optimization of the orientation of water molecules in either the presence or absence of the bound ligand has any effect on the accuracy of docking predictions. We have observed a statistically significant overall increase in accuracy when water molecules are included during docking simulations and have found this to be independent of the method of optimization of the orientation of water molecules. These results confirm the importance of including water molecules whenever possible in a ligand-protein docking simulation. Our findings also reveal that prior optimization of the orientation of water molecules, in the absence of any bound ligand, does not have a detrimental effect on the improved accuracy of ligand-protein docking. This is important, given the use of docking simulations to predict the binding modes of new ligands or drug molecules.     

Biased retrieval of chemical series in receptor-based virtual screening

Using the kinases in the DUD dataset and an in-house HTS dataset from PI3K-γ, receptor-based virtual screening experiments were performed using Glide SP docking. While significant enrichments were observed for eight of the nine targets in the set, more detailed analyses highlighted that much of the early enrichment (10–80%) is the result of retrieval of a single cluster of active compounds. This biased retrieval was not necessarily due to early enrichment of the cluster containing the co-crystallized ligand. Virtual screening validation studies could thus benefit from including cluster-based analyses to assess enrichment of diverse chemotypes.     

Ligand- and anion-controlled formation of silver alkynyl oligomers from soluble precursors

Novel silver(I) alkynyl cluster complexes ([Ag5(bpy)4(C [triple bond] CBu(t))2](3+), [Ag8(bpy)6(C [triple bond] CBu(t))4](4+), and [Ag 12(bpy)4(C [triple bond] CBu(t))6(CF3CO2)6]) have been synthesized by reacting soluble polymeric precursors with bipyridine ligands, and control of the nuclearity can be achieved by varying the molar ratio of the reactants and using different types of anions.     

Acetylcholine detection at micromolar concentrations with the use of an artificial receptor-based fluorescence switch

An inclusion complex between water-soluble p-sulfocalix[n]arene (Cn, n=4, 6, 8) and the chromophore trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium-p-toluenesulfonate (D) formed the basis for a highly sensitive sensor for the selective detection of neurotransmitter acetylcholine (ACh). Formation of the [Cn.D] complex (Ka=approximately 10(5) M(-1)) was accompanied by a drastic increase (up to 20-60-fold) in the chromophore relative quantum yield and by a large hypsochromic shift of the emission band maximum. The observed optical effects are fully reversible: ACh displaces the chromophore molecules from the calixarene cavity as shown by the reappearance of the free chromophore emission band. Formation and dissociation of the complex were studied by fluorescence, 1H NMR, and UV-vis absorption spectroscopies. The [Cn.D] complex is capable of sensing ACh selectively in solution at sub-micromolar concentrations. Immobilization of monocarboxyl p-sulfocalix[4]arene (C4m) on an oxide-containing silicon surface is in keeping with its properties, such as chromophore binding and the ability of the immobilized inclusion complex to detect ACh. The unique [Cn.D] complex optical switching paves the way for application in ACh imaging and optoelectronic sensing.     

Biosensor analysis of beta-lactams in milk: comparison with microbiological, immunological, and receptor-based screening methods

Two recently developed surface plasmon resonance biosensor assays for detection of beta-lactams in milk were used to screen raw producer milk samples. Both assays use a beta-lactam receptor protein with carboxypeptidase activity for detection. The results of the biosensor assays were compared with those of various commercial screening tests, i.e., the Delvotest SP, Penzym S, Beta-STAR, SNAP, and Parallux. The results of the 2 biosensor assays showed good agreement with those of the other screening tests. Of 195 analyzed milk samples, the results of only 5 samples differed between the assays. Additionally, 30 milk samples with both negative and positive results in the screening assays were analyzed by liquid chromatography for identification and quantification of any beta-lactam residues. All screening tests showed 0% false-negative results with 15 incurred samples containing between 4.0 and 268 microg/kg penicillin G. The biosensor assays showed 27% positive results (false violatives) with 15 producer milk samples containing penicillin G concentrations between 0 and 3.6 microg/kg, i.e., below maximum residue limit. This figure varied between 27 and 53% for the other screening tests.     

Automated docking with grid-based energy evaluation

The ability to generate feasible binding orientations of a small molecule within a site of known structure is important for ligand design. We present a method that combines a rapid, geometric docking algorithm with the evaluation of molecular mechanics interaction energies. The computational costs of evaluation are minimal because we precalculate the receptor-dependent terms in the potential function at points on a three-dimensional grid. In four test cases where the components of crystallographically determined complexes are redocked, the “force field” score correctly identifies the family of orientations closest to the experimental binding geometry. Scoring functions that consider only steric factors or only electrostatic factors are less successful. The force field function will play an important role in our efforts to search databases for potential lead compounds.     

An acetylcholine receptor-based biosensor for the detection of cholinergic agents

A practical, acetylcholine receptor-based prototype biosensor is reported. The biosensor utilizes a polymeric film containing the receptor and appropriate stabilizers to coat an interdigitated electrode transducer. Upon binding of specific cholinergic ligands to the immobilized receptor, changes occur in the electrical field of the electrodes proportional to the amount of cholinergic agent present. The biosensor can detect micro- to nano-gram quantities of cholinergic ligands per ml within 1–5 s. The biosensor can be recycled with acetylcholine and is stable for at least 72 h during use and over 6 months in storage at normal temperatures. The cholinergic biosensor represents the first instance of a biosensor based on a physiologically active receptor for the detection of a class of chemical compounds.     

A new strategy for molecular modeling and receptor-based design of carborane containing compounds

Difficulties associated with computer-aided molecular design (CAMD) of carborane containing molecules have hampered drug development in boron neutron capture therapy (BNCT). A new approach of modeling and docking of carborane containing molecules with the readily available software packages , and is described. This new method is intended as a guide for boron chemists interested in using CAMD of carborane containing agents for medical applications such as BNCT.     

Pocket v.2: further developments on receptor-based pharmacophore modeling

A deriving pharmacophore model from the three-dimensional structure of a target protein provides helpful information for analyzing protein-ligand interactions and further improvement of ligand binding affinity. A standalone program, Pocket v.2, has been developed based on the original Pocket module in the de novo drug design program LigBuilder. Pocket v.2 is able to derive a pharmacophore model directly from a given protein-ligand complex structure without human intervention. Key features in the pharmacophore model are automatically reduced to a reasonable number. Pocket v.2 has been applied to several case studies, including cyclin dependent kinase 2, HIV-1 protease, estrogen receptor, and 17beta-hydroxysteroid dehydrogenase. It well reproduced previously published pharmacophore models in all of these cases. One notable feature of Pocket v.2 is that it can tolerate minor conformational changes on the protein side upon binding of different ligands to give a consistent pharmacophore model. For different proteins accommodating the same ligand, Pocket v.2 gives similar pharmacophore models, which opens the possibility to classify proteins with their binding features.     

Molecular docking with ligand attached water molecules

A novel approach to incorporate water molecules in protein-ligand docking is proposed. In this method, the water molecules display the same flexibility during the docking simulation as the ligand. The method solvates the ligand with the maximum number of water molecules, and these are then retained or displaced depending on energy contributions during the docking simulation. Instead of being a static part of the receptor, each water molecule is a flexible on/off part of the ligand and is treated with the same flexibility as the ligand itself. To favor exclusion of the water molecules, a constant entropy penalty is added for each included water molecule. The method was evaluated using 12 structurally diverse protein-ligand complexes from the PDB, where several water molecules bridge the ligand and the protein. A considerable improvement in successful docking simulations was found when including flexible water molecules solvating hydrogen bonding groups of the ligand. The method has been implemented in the docking program Molegro Virtual Docker (MVD).     

Ligand-receptor docking with the Mining Minima optimizer

The optimizer developed for the Mining Minima algorithm, which uses ideas from Genetic Algorithms, the Global Underestimator Method, and Poling, has been adapted for use in ligand-receptor docking. The present study describes the resulting methodology and evaluates its accuracy and speed for 27 test systems. The performance of the new docking algorithm appears to be competitive with that of previously published methods. The energy model, an empirical force field with a distance-dependent dielectric treatment of solvation, is adequate for a number of test cases, although incorrect low-energy conformations begin to compete with the correct conformation for larger sampling volumes and for highly solvent-exposed binding sites that impose little steric constraint on the ligand.     

Ligand- and anion-directed assembly of exo-coordinated mercury(II) halide complexes with O2S2-donor macrocycles

Assembly reactions of mercury(II) halides (Cl, Br, and I) with two O2S2 macrocycles (L(1) and L(2)) having different interdonor (S...S) distances were investigated, and four types of supramolecular complexes (1-4b) were obtained depending on the S...S distances as well as the size of the halide anions. Photoluminescence of these compounds was also studied.