POLYMER CHEMISTRY

European Journal of Pharmaceutical Sciences, 2013

A simple molecular modeling method for the characterization of polymeric drug carriers is presented. Six biodegradable polymers have been investigated as drug carriers using molecular simulations: L-polylactide, D-polylactide, chitosan, polyglycolic acid, polyethylene glycol and cellulose. Cyclosporine A has been chosen as a model drug substance. Classical molecular dynamics and docking calculations were employed to model and predict polymer-drug interactions. These interactions have been analyzed by non-bond interaction energy and interaction parameter calculated using Flory-Huggins theory. Flexibility of polymer chains has been characterized by the change of gyration radius along the molecular dynamics trajectory. The relationship between mixing energy, chain length and chain flexibility has been revealed for each polymer/drug system.

Journal of Computer-Aided Molecular Design, 2012

Multipoint interactions between synthetic and natural polymers provide a promising platform for many topical applications, including therapeutic blockage of virus-specific targets. Docking may become a useful tool for modelling of such interactions. However, the rigid docking cannot be correctly applied to synthetic polymers with flexible chains. The application of flexible docking to these polymers as whole macromolecule ligands is also limited by too many possible conformations. We propose to solve this problem via stepwise flexible docking.

Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.

Journal of Computer-Aided Molecular Design, 2014

In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1] 3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1] 3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main dockingpredicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention. The binding selectively driven by counter-ionisable (cationic) Lys574/Arg579 at L1, His564 at L2, and Arg567 at L3, respectively. J Comput Aided Mol Des (2014) 28:647-673 649

Advanced Drug Delivery Reviews, 2001

Polymers are ubiquitous components of products manufactured for medical and pharmaceutical applications. Widely used commodity polymers were the first polymers to be utilised in biomedical applications. These polymers were not developed with biocompatibility established at the onset and many speciality polymers have been developed in recent years to begin to meet the multifaceted demands for medical development, the optimisation of structure-property correlations and ultimately, clinical use. In the broader area of materials research, combinatorial or high throughput strategies used for drug development are recognised to have potential for discovery and process development. Much of the application of combinatorial chemistry in drugs research has been dependent on the use of polymeric reagents, substrates and supports. The chemistry of the reactions on polymers in solid and liquid phases have also played a major role in combinatorial drugs research. There is considerable interest in combinatorial materials research and this review outlines how this research may be applied for biomedical polymer development.

Pharmacology & Therapeutics, 2000

Drug design is a creative act of the same magnitude as composing, sculpting, or writing. The results can touch the lives of millions, but the creator is rarely one scientist and the rewards are distributed differently in the arts than in the sciences. The mechanisms of creativity are the same, i.e., incremental (plodding from darkness to dawn) or sudden (the "Eureka" effect) realization, but both are poorly understood. Creativity remains a human characteristic, but it is directly related to the tools available, especially computer software and hardware. While modelling software continues to mature, very little new has evolved in terms of hardware. Here, we discuss the history of molecular modelling and describe two novel modelling tools, a haptic device and a program, SCULPT, to generate solid molecular models at atomic resolution.

Molecular Diversity, 1996

A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (a-helix, 13-sheets, etc.; 0, ~ space) and those related to three-dimensional presentation of side-chain moieties (topography;)~ (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems.

Trends Pharmacol Sci, 1994

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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

This article is an overview on the computer aided drug designing, which can predict experimental results with reasonable accuracy and reduced time, cost and equipment. It identifies the new compound or optimize the lead compound that show significant inhibitory activity against a biological receptor. It provides specicifity of drug on the target whether it is ligand based or structure based screening. Computational molecular modeling methods attempt to predict these interactions and thus the binding affinities and conformation of protein-ligand complexes. Introduction to computer-aided drug design (CADD): In recent years, the field of computer-aided drug design (CADD) has grown rapidly, enhancing our understanding of complex biological processes and protein-ligand interactions. CADD can predict experimental results with reasonable accuracy and reduced time, cost and equipment. CADD continuously enhances the progress of drug discovery and refinement of therapeutic agents with many successful examples. Computational drug design has been widely used in the pharmaceutical industry to either identify new compounds or optimise lead compounds that show significant inhibitory activity against a target biological receptor. A small number of examples of these uses are included in Table 1. It is known that chemicals can bind to biological receptors and produce a specific therapeutic response. Drug design is often targeted against receptor molecules which are proteins. The ability of a ligand to bind to a specific protein is related to molecular structure, orientation and conformation. During the binding process, there are enthalpy and entropy changes in the protein-ligand system, associated with alteration of both intra-and inter-molecular structures of protein and ligand. W WO OR RL LD D J JO OU UR RN NA AL L O OF F P