TASK Quarterly   Scientific Bulletin of the Centre of Informatics - Tricity Academic Supercomputer & networK   ISSN 1428-6394

    4/98 "Computer Modelling in Rational Drug Design"

    Guest editor: Prof. Edward Borowski,
    Technical University of Gdansk, Poland

    Some info about Symposia on Molecular Aspects of Chemotherapy
    Another info about ISQBP meeting "Molecular Structure and Dynamics in Biology", Elba (Italy) September 8-11, 1998 

    • J.Mazerski, E.Borowski, Molecular Modelling in Rational Design of Some Anti-Tumor and Antifungal Agents - abstract
    • G.Naray-Szabo, P.Matyus, Electrostatics in Computer-Aided Drug Design, - abstract
    • G.Alagona, C.Ghio, S.Monti, Modelling Drug-Receptor Interactions in an Average Binding Site for NK2, - abstract
    • J.Ciarkowski, C.Czaplewski, R.Kazmierkiewicz, E.Politowska, Targets for Majority of Drugs: G Protein-Coupled Receptors - Their Structure and Interactions with Bioligands, - abstract
    • K.Kubica, Polar Head Charge of Membrane Modifiers and their Biological Activity. Monte Carlo Simulation Studies, - abstract

    Contributed Papers
    • M.Rewienski, Methods of Solving Operator Eigenproblems in Parallel Distributed Memory Systems as Applied in Electromagnetics, - abstract

    From the History of Science and Technology in Ancient Gdansk


  • J.Mazerski, E.Borowski, Molecular modelling in rational design of some chemotherapeutics agents
  • In this paper we present our approaches and results concerning application of molecular modelling techniques in the design of new chemotherapeutic agents for the control of eukariotic systems, comprising compounds for the treatment of systemic fungal infections and tumor deseases. In the case of anti-tumor agents we focused our attention on molecular properties of natural and synthetic anthraquinones. In the area of antifungal compounds we adopted two approaches. In one of them we examine molecular nature of undesirable properties of polyene macrolide antifungal antibiotic - amphotericin B using molecular modelling techniques. Another approach was aimed at the development of selective inactivator of glucosamine synthase, a novel target for antifungal compounds. In this problem we have used computational chemistry methods to identify structural features responsible for the selective inactivation of the target enzyme.

  • G.Naray-Szabo, P.Matyus, Electrostatics in Computer-Aided Drug Design
  • Hydrogen bonds and charge-charge interactions, determined by molecular electrostatics, play essential role in biopolymer-ligand associations. Accordingly, electrostatics is crucial in the qualitative and quantitative characterisation of the binding of drugs to their target molecules. In the following, we will give an account on the role of molecular electrostatics in a drug design, laying emphasis on our own work. We will survey the most important computation methods of molecular electrostatic potentials, then outline basic aspects of molecular recognition: steric, electrostatic and hydrophobic complementarity. On the basis of the complementarity, we will also define molecular similarity and discuss various applications of these concepts to the treatment of protein-ligand interactions and a rational drug design. Special attention will be paid to a receptor mapping and to a comparative molecular field analysis, with some our recent applications. A further important point will be the molecular electrostatic field (potential gradient) as a hydrophobicity measure. We will argue that the hydrophobic complementarity and similarity can be treated on the basis of matching regions of the interacting molecules that are characterised by a similar magnitude of the electrostatic field. The concept of the electrostatic complementarity will be extended to enzyme-substrate interactions, providing a firm basis for the quantitative estimation of catalytic rate enhancement.

  • G.Alagona, C.Ghio, S.Monti, Modelling Drug-Receptor Interactions in an Average Binding Site for NK2
  • A tentative procedure applied to the search for a new antagonist of neurokinin A (NKA) is presented. In parallel a tentative 3-D model of the NK2 receptor was created, using bacteriorhodopsin (BRD) as a template. The residue substitutions were performed in BRD to obtain the sequence for NK2R_H and the seven a-helical segments were optimized forcing the a-helical backbone to match the corresponding aligned parts of BRD, while the arrangements of the side chains were model built based on available site-directed mutagenesis studies. Constrained MM and molecular dynamics simulations were carried out H-bonding a low energy conformer of the known drugs to residues in the receptor site, allowing both the receptor site and drugs to relax. The Connolly surface for each ligand allowed to determine an "average" binding site in which all the low energy conformers of known and prospective drugs were docked and classified according to a statistical index. The whole procedure was repeated exploiting the lately published structure of an actual G protein coupled receptor as a better template, thus producing a cavity in the binding site to directly dock the drugs. Corollary validations of the force fields used are also mentioned. In addition intra- and intermolecular interactions suitable to produce more active drugs were evaluated.

  • J.Ciarkowski, C.Czaplewski, R.Kazmierkiewicz, E.Politowska, Targets for Majority of Drugs: G Protein-Coupled Receptors - Their Structure and Interactions with Bioligands
  • G protein-coupled receptors (GPCRs) are the most frequent targets for many drugs. They form the largest superfamily of integral membrane proteins, of which more than 1000 members have the following common features: (i) All GPCRs form 7 hydrophobic a-helices of length ~38 (25 amino acids, 7 turns) along a single chain. The consecutive helices alternatively cross the membrane, starting from the extracellular side, so that they form a heptahelical transmembrane domain interwoven with 6 loops, of which the even ones plus the N-terminus create the receptor's extracellular domain while the odd ones plus the C-terminus form its intracellular domain. (ii) All GPCRs are stimulated by diverse extracellular (primary) signals. (iii) Stimulated GPCRs convey the primary signals via their transmembrane and intracellular domains to the cytosolic peripheral heterotrimeric GTP-binding proteins (G proteins), mediating the signal's further transduction to various cellular second messenger systems. A current status of structural studies on GPCRs, consisting of low ~7.5 resolution experimental structures and supplementary molecular modeling, is outlined. Subsequently, some results of authors' own work on studying essential interactions of the V2 vasopressin renal receptor (V2R) with its agonist [Arg8]Vasopressin (AVP) and selected antagonists are presented, as well as their possible impact on the biological signal transduction is discussed. Finally, perspectives for future developments are sketched.

  • K.Kubica, Polar Head Charge of Membrane Modifiers and their Biological Activity. Monte Carlo Simulation Studies
  • On the basis of the 10-state Pink model, the effect of the polar head charge of amphiphilic modifier molecules has been discussed. It was shown, that for small concentrations of anionic and cationic compounds inserted into a layer composed of electroneutral lipids the electrostatic interaction, in spite of the long-range character, can be limited to the nearest neighbour interaction. Computer simulation results suggest, that the gel-fluid transition temperature can be lowered or raised by a proper selection of anionic-cationic amphiphilic modifiers. Moreover, the effect of ionic strength of the membrane medium and dielectric permeability of the hydrophobic part of membrane, where a shift of the dielectric constant from 5 to 80 occurred, has been studied. It was also shown that addition of alkyl molecules to the membrane, which are the counterions of alkyl modifier molecules added earlier, almost doubles the number of incorporated membrane modifiers. Membrane permeability analysis shows that membrane permeability, at temperatures lower than the gel-fluid transition temperature, should be more related to the number of small domains (cluster area) and less to the interfacial area.

  • M.Rewienski, Methods of Solving Operator Eigenproblems in Parallel Distributed Memory Systems as Applied in Electromagnetics
    This study presents numerical methods of solving operator eigenproblems, focusing on their applications in electromagnetics. The discussion concentrates on the analysis of new iterative algorithms or modifications of the existing ones, which are capable of finding a few eigenvalues from the point spectrum of a non-symmetric operator. The salient feature of the considered methods is a low computational cost and memory complexity as compared to alternative solutions. This paper also presents implementations of the investigated algorithms in parallel distributed memory systems, based on the message-passing parallel programming model and providing portable parallel eigensolvers. The discussion of the applied designs of the parallel algorithms is supported by the presentation of the results of performance tests in selected distributed memory environments, including scalable parallel supercomputer systems and networks of workstations. The results of these tests confirm high efficiency of the eigensolvers in the considered parallel environments. In this study attention is also drawn to the question of the applicability of the eigensolvers to problems of modelling of electromagnetic fields in dielectric waveguides. The results of numerical tests validating the methods in these applications determine the scope of problems which may be most effectively solved using the specific eigensolvers.