MTD-ADJ: A multiconformational minimal topologic difference for determining bioactive conformers using adjusted biological activities

The active conformation is part of a conformational mixture with experimental activity Yexp, and is used in QSAR studies to extract more information regarding the ligand-receptor interaction. To reflect the relative amount () of the active conformation, we adjust Yexp : Yadj = Yexp - log . We establish a quantitative structure-activity relationship (QSAR) between Yadj and 3D conformational characteristics for the acetylcholinesterase (AChE) hydrolysis rates of 25 acetic esters. The 3D-QSAR model was obtained using the adjusted multiconformational minimal steric/topologic difference (MTD-ADJ) method, optimizing the receptor map based on Yadj for each conformer. Yadj was updated during each step of the optimization process. and Yadj are based on the Boltzmann distribution calculated using AM1 (MOPAC 6.0) relative energies of the COSMIC 90 derived conformers. The MTD-ADJ results are: (i) the 3D-QSAR models obtained by this procedure have significant statistical parameters and are similar to the unadjusted (MTD-MC, using Yexp) models; (ii) the selected bioactive conformations are extended, occupy cavity vertices and, for the same structures, have the same MTD value; and (iii) the optimized conformational map of the neutral ligands obtained from the MTD-ADJ model fits well in the active site of the crystallographic structure of AChE (from Torpedo californica). We propose a neutral ligands binding site model for AchE. Our results show that MTD-ADJ, which can be implemented in any 3D-QSAR method, is capable of providing additional information regarding the active conformations, and can be used to gain further insight into the ligand-receptor models for which no structural data are available.     

Scaffold topologies. 2. Analysis of chemical databases

We have systematically enumerated graph representations of scaffold topologies for up to eight-ring molecules and four-valence atoms, thus providing coverage of the lower portion of the chemical space of small molecules (Pollock et al. J. Chem. Inf. Model., this issue). Here, we examine scaffold topology distributions for several databases: ChemNavigator and PubChem for commercially available chemicals, the Dictionary of Natural Products, a set of 2742 launched drugs, WOMBAT, a database of medicinal chemistry compounds, and two subsets of PubChem, "actives" and DSSTox comprising toxic substances. We also examined a virtual database of exhaustively enumerated small organic molecules, GDB (Fink et al. Angew. Chem., Int. Ed. 2005, 44, 1504-1508), and we contrast the scaffold topology distribution from these collections to the complete coverage of up to eight-ring molecules. For reasons related, perhaps, to synthetic accessibility and complexity, scaffolds exhibiting six rings or more are poorly represented. Among all collections examined, PubChem has the greatest scaffold topological diversity, whereas GDB is the most limited. More than 50% of all entries (13 000 000+ actual and 13 000 000+ virtual compounds) exhibit only eight distinct topologies, one of which is the nonscaffold topology that represents all treelike structures. However, most of the topologies are represented by a single or very small number of examples. Within topologies, we found that three-way scaffold connections (3-nodes) are much more frequent compared to four-way (4-node) connections. Fused rings have a slightly higher frequency in biologically oriented databases. Scaffold topologies can be the first step toward an efficient coarse-grained classification scheme of the molecules found in chemical databases.     

A Comparative Loading and Release Study of Vancomycin from a Green Mesoporous Silica

Since its first use as a drug delivery system, mesoporous silica has proven to be a surprisingly efficient vehicle due to its porous structure. Unfortunately, most synthesis methods are based on using large amounts of surfactants, which are then removed by solvent extraction or heat treatment, leading to an undesired environmental impact because of the generated by-products. Hence, in the present study, we followed the synthesis of a silica material with a wormhole-like pore arrangement, using two FDA-approved substances as templates, namely Tween-20 and starch. As far as we know, it is the first study using the Tween-20/starch combo as a template for mesoporous silica synthesis. Furthermore, we investigated whether the obtained material using this novel synthesis had any potential in using it as a DDS. The material was further analyzed by XRD, TEM, FT-IR, N₂ adsorption/desorption, and DLS to investigate its physicochemical features. Vancomycin was selected as the active molecule based on the extensive research engaged towards improving its bioavailability for oral delivery. The drug was loaded onto the material by using three different approaches, assuming its full retention in the final system. Thermal analysis confirmed the successful loading of vancomycin by all means, and pore volume significantly decreased upon loading, especially in the case of the vacuum-assisted method. All methods showed a slower release rate compared to the same amount of the pure drug. Loadings by physical mixing and solvent evaporation released the whole amount of the drug in 140 min, and the material loaded by the vacuum-assisted method released only 68.2% over the same period of time, leading us to conclude that vancomycin was adsorbed deeper inside the pores. The kinetic release of the three systems followed the Higuchi model for the samples loaded by physical mixing and vacuum-assisted procedures, while the solvent evaporation loading method was in compliance with the first-order model.     

Current trends in lead discovery: are we looking for the appropriate properties?

The new drug discovery paradigm is based on high-throughput technologies, both with respect to synthesis and screening. The progression HTS hits lead series candidate drug marketed drug appears to indicate that the probability of reaching launched status is one in a million. This has shifted the focus from good quality candidate drugs to good quality leads. We examined the current trends in lead discovery by comparing MW (molecular weight), LogP (octanol/water partition coefficient, estimated by Kowwin [17]) and LogSw (intrinsic water solubility, estimated by Wskowwin [18]) for the following categories: 62 leads and 75 drugs [11]; compounds in the development phase (I, II, III and launched), as indexed in MDDR; and compounds indexed in medicinal chemistry journals [ref. 20], categorized according to their biological activity. Comparing the distribution of the above properties, the 62 lead structures show the lowest median with respect to MW (smaller) and LogP (less hydrophobic), and the highest median with respect to LogSw (more soluble). By contrast, over 50% of the medicinal chemistry compounds with activities above 1 nanomolar have MW > 425, LogP > 4.25 and LogSw < -4.75, indicating that the reported active compounds are larger, more hydrophobic and less soluble when compared to time-tested quality leads. In the MDDR set, a progressive constraint to reduce MW and LogP, and to increase LogSw, can be observed when examining trends in the developmental sequence: phase I, II, III and launched drugs. These trends indicate that other properties besides binding affinity, e.g., solubility and hydrophobicity, need to be considered when choosing the appropriate leads.     

Evaluation of the Compatibility of EPDM and IIR I. Specific heat capacity

The thermal effect of mixing of EPDM and IIR was studied by differential scanning calorimetry over the temperature range between 335 and 435 K. O'Neill's method was used for calculating the specific heat capacity with alumina as standard. The greater the butyl rubber content, the lower the heat capacity. The presence of butyl rubber induces a marked thermal instability because of isobutylene units. It is possible that a rearrangement occurs in the molecular sequence, accompanied by secondary reactions involving free radicals. The contribution of each component to the cP of the tested polymeric systems is discussed. Differences between theoretical and experimental specific heat capacities increase as the operation temperature is raised. The relationship between the contributions of the two components to the specific heat capacity values of mixtures can be described by a first order equation, named the law of reciprocal thermal affinity. This aspect can be ascribed to the interaction of various reacting entities, which form certain units with low molar heat capacity. This revised version was published online in July 2006 with corrections to the Cover Date.     

The Design of Leadlike Combinatorial Libraries

The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence of affinity enhancement. Hits with affinity at μM levels discovered by screening leadlike libraries allow scope for this optimization process, as shown schematically by the distributions of M(r) for a leadlike library (1), oral drugs (2), and a typical combinatorial chemistry library (3). y=percentage with a particular molecular weight.     

On exchange coupling and bonding in the Gd2@C80 and Gd2@C79N endohedral dimetallo-fullerenes

A series of computational experiments performed with various methods belonging to wave-function and density functional theories approaches the issue of bonding regime and exchange coupling in the title compounds. Gd₂@C₈₀ is computed with a very weak exchange coupling, the sign depending on the method, while Gd₂@C₇₉N has resulted with a strong coupling and ferromagnetic ground state, irrespective of the computational approach. The multi-configuration calculation and broken symmetry estimation are yielding closely coincident coupling constants, of about J ～ 400 cm^?1. No experimental estimation exists, but the ferromagnetic ground state of Gd₂@C₇₉N is confirmed from paramagnetic resonance data. The different behaviour is due to particularities of electron accommodation in the orbital scheme. The exchange effects localised on atom lead to preference for parallel alignment of the electrons placed in the 4f and 5d lanthanide shells, determining also a ferromagnetic inter-centre coupling. The structural insight is completed with a ligand field analysis of the density functional theory results in the context of frozen density embedding. The energy decomposition analysis of bonding effects is also discussed. Finally, with the help of home-made codes (named Xatom+Xsphere), a model for the atom encapsulated in a cage is designed, the exemplified numeric experiments showing relevance for the considered endohedral metallo-fullerene issues.     

Capillary gas chromatography-mass spectrometry of volatile and semi-volatile compounds of Salvia officinalis

The essential oil and infusion of Salvia officinalis leaves have been widely applied in traditional medicine since ancient times and nowadays subjected to extensive research of their antibacterial, antiviral and cytotoxic properties. This paper shows chemical composition data of S. officinalis leaves essential oil isolated by steam distillation using a Clevenger-type apparatus. Also, the paper presents the chemical content of volatile and semi-volatile compounds of S. officinalis leaves infusion. The volatile and semi-volatile compounds of S. officinalis leaves infusion were isolated by solid-phase extraction (SPE) and liquid-liquid extraction with hexane and dichloromethane. SPE was carried out on 500 mg octadecylsilane (C18) cartridges and elution with dichloromethane. Liquid-liquid extraction was performed with hexane and dichloromethane. The essential oil in dichloromethane and infusion extracts in hexane and dichloromethane were analyzed by gas chromatography coupled with mass spectrometry. The quantitative results obtained by solid-phase extraction and liquid-liquid extraction showed that SPE on C18 performed the highest recovery of the volatile compounds from infusion sample.