Soheila Anzali

The multifunctional role of ectoine as a natural cell protectant

The protective properties of ectoine, formerly described for only extremophilic microorganisms, can be transferred to human skin. Our present data show that the compatible solute ectoine protects the cellular membrane from damage caused by surfactants. Transepidermal water loss measurements in vivo suggest that the barrier function of the skin is strengthened after the topical application of an oil in water emulsion containing ectoine. Ectoine functions as a superior moisturizer with long-term efficacy. These findings indicating that ectoine is a strong water structure-forming solute are explained in silico by means of molecular dynamic simulations. Spherical clusters containing (1) water, (2) water with ectoine, and (3) water with glycerol are created as model systems. The stronger the water-binding activity of the solute, the greater the quantity of water molecules remaining in the cluster at high temperatures. Water clusters around ectoine molecules remain stable for a long period of time, whereas mixtures of water and glycerol break down and water molecules diffuse out of the spheres. On the basis of these findings, we suggest that the hydrogen bond properties of solutes are not solely responsible for maintaining the water structure form. Moreover, the particular electrostatic potential of ectoine as an amphoteric molecule with zwitterionic character is the major cause for its strong affinity to water. Because of its outstanding water-binding activity, ectoine might be especially useful in preventing water loss in dry atopic skin and in recovering skin viability and preventing skin aging.

The comparison of geometric and electronic properties of molecular surfaces by neural networks: Application to the analysis of corticosteroid-binding globulin activity of steroids

SummaryIt is shown how a self-organizing neural network such as the one introduced by Kohonen can be used to analyze features of molecular surfaces, such as shape and the molecular electrostatic potential. On the one hand, two-dimensional maps of molecular surface properties can be generated and used for the comparison of a set of molecules. On the other hand, the surface geometry of one molecule can be stored in a network and this network can be used as a template for the analysis of the shape of various other molecules. The application of these techniques to a series of steroids exhibiting a range of binding activities to the corticosteroid-binding globulin receptor allows one to pinpoint the essential features necessary for biological activity.

The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5

Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.

2. Endothelin antagonists : Evaluation of 2,1,3-benzothiadiazole as a methylendioxyphenyl bioisoster

The methylendioxyphenyl group is present in a number of endothelin receptor antagonists thus far reported. By means of a Kohonen neural network we discovered with a benzothiadiazole a bioisosteric replacement instead. This group should be devoid of the negative metabolic interactions with cytochrome P450 ascribed to methylendioxyphenyl in vivo. The synthesis of a potent benzothiadiazole analogue EMD 122801 together with in vitro studies of different methylendioxyphenyl, benzothiadiazole and benzofurazan derivatives is described.

3. Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist

The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding affinity and functional antagonism [IC50 = 3.2 x 10(-11) M, pA2 = 9.5 (ETA)] and inhibited the ET-1 induced pressor response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys.

Evaluation of Molecular Surface Properties Using a Kohonen Neural Network

In this chapter the use of a Kohonen map in structure–activity relationship (SAR) and drug design is described. A transformation of 3D-molecular surfaces into 2D-Kohonen maps is realized on the basis of an application of a Kohonen neural network. The trained neurons of the Kohonen maps are then colored according to the molecular electrostatic potential (MEP) values on the van der Waals surfaces. A template approach is presented for the comparison of the shape and the MEP values of a molecule with that of a reference structure. Applications of these methods are illustrated with datasets of ryanodines, cardiac glycosides, and steroids. The results indicate that the Kohonen neural network may be a useful tool for the investigation of large datasets of molecules and for the fast and accurate comparison of molecular electrostatic potentials and shapes within a series of compounds.

Bioisosterism of fluorine and cyano as indole substituents. Theoretical, in vitro and in vivo examination

Fluorine substitution modifies structural attributes and often induces unexpected effects. When substituting fluorine with cyano in position 5 of the indole in indole-butyl-amines, the properties of the compounds proved to be very comparable. In vitro target-profile, metabolism, and in vivo activity in the ultrasonic vocalisation test indicate bioisosterism between the two substituents.

A Systemsatic Approach to Finding New Lead Structures Having Biological Activity

The development of a new drug is an enormously largescale and expensive process. Thus, computer simulation methods become to play an increasing role in the development of new pharmacologically active compounds. Most of the commercial software presently used, comes from the U.S.; their deficits have become more and more obvious during the last years. Several methods have been developed in our project to alleviate these problems. The search for new lead structures starts with analyzing large databases of compounds (several hundreds of thousands up to several millions of compounds) zeroing into a few promising structures by increasing sophistication of structure representation. Due to the large number of chemical compounds, a systematic scheme for representing structures was developed: The starting point is the constitution, followed by calculation of the 3D structure, then including conformational flexibility. At each step, a variety of chemical properties can be taken into consideration. In addition, new programs have been developed for the treatment of conformational flexibility. The methods presented are also useful for other areas of application dealing with chemical information. Thus, it was shown that one of these new structure representations is suitable for treating problems in combinatorial synthesis. Neural networks and genetic algorithms are highly important for the investigation of the correlation between structure and biological activity. Complex relationships and huge amounts of data can be processed by these methods. Implementation of these procedures on highly parallel computers has proved that datasets of several hundreds of thousands of structures can be treated with acceptable computation times.