CompChem

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Revision as of 07:39, 6 July 2011

General Information

• Application's name : Quantum Mechanical, Molecular Mechanics, and Molecular

Dynamics computation in chemistry

• Virtual Research Communities : Computational Chemistry Applications
• Scientific contact : Ivan Juranic, ijuranic@chem.bg.ac.rs
• Technical contact : Ivan Juranic, ijuranic@chem.bg.ac.rs
• Developers : Ivan Juranic, Univeristy of Belgrade, Faculty of Chemistry, Republic of Serbia
• Web site :

Application and Short Description

The project deals with modeling of molecular structure and mechanism of chemical reactions. Quantum mechanical, ab-initio, and DFT calculations will be applied for molecules that consist up to 250 atoms. Molecular mechanics and molecular dynamics simulation will be used for examination of ligands interaction with proteins and other biomacromolecules, as well as for conformational sampling of small molecules in explicit solvent cluster. In such simulations size of ligands should be up to 300 atoms; while biomacromolecule can have size of more than ten thousands of atoms. In the present stage, simulations were done by NAMD2.7.

Our research is directed toward:

a) examination of the free-energy landscapes of highly potent and very selective antitumor agents, named CSAB (see Journal of Medicinal chemistry, 48, 5600-5603, (2005); The XVI European Symposium on Quantitative Structure-Activity Relationships and Molecular Modelling, 10-17 September 2006 Mediterranean Sea / Italy. Final program& General Information pp. 274-275; and The 18th European Symposium on Quantitative Structure-Activity Relationships, 19-24 September 2010, Rhodes, Greece. Final Program & Abstract Book, pp. 278-279), in explicit solvent clusters, having different dielectric constants, H-bonding ability, and polarity, by medium lasting (~ 30ns) molecular dynamic simulations coupled with adaptive biasing force calculation;

b) Molecular dynamics simulations (~ 80 ns each) for “approach and entrance” of the group of compounds, which act as dual acetylcholine esterase (AChE) inhibitors, to enzyme active site. Whole systems (enzyme + inhibitor) for each compound are embedded in properly sized (large) solvent cluster. Last stage of each simulation includes adaptive biasing force calculation.

Several components of this approach require massive study of the vast parameter space and include tightly-coupled simulations with large memory requirements. Testing, benchmarking and production runs of some of the components can be done on standard Grid-type Linux clusters, but the core components require low-latency parallel environment. Postprocessing of trajectories, as well as output of (coupled) free-energy calculations, are also often memory demanding, so it is suitable to do such analysis on the nodes associated with the cluster where simulation were performed.

Problems Solved

Both group of compounds described in previous section are designed, synthesized and biologically tested by our group. First group of compounds represent entirely new chemotypes, as well as new chemical entities; while second group comprises new chemical entities.

Simulations described in application description under a) – CSAB – should give insight of selectivity of compounds (potency toward tumors/ toxicity toward healthy cells), which are, according to existing experimental data, highly correlated with molecular flexibility. Also, we try to find most appropriate force field among those that are available, for this type of simulation; and to examine advantages and possible disadvantages of methods of calculation used, which are relatively novel and were not applied on the systems comparable with ours, so far.

Simulations described in application description under b) – interaction of dual AChE inhibitors with the enzyme – should give insight on intramolecular interactions between the enzyme and examined compounds, and should give hint for most favorable structural modifications of compounds in order to improve their potency. To the best of our knowledge similar simulations were not reported in literature so far.

Scientific and Social Impact

Within major applicable goals of scientific knowledge now and in close future, few are priority: novel energy sources, novel materials, and novel medicines. First two goals arise from decreasing amount of fuels originated from natural sources in the World; the third one is ultimate consequence of the rise of population and growing older population in the developed countries. Developing of new medicines in a rational way includes recognition of target (enzyme, protein) that causes a specific physiological disorder, and developing of molecules that could modify those targets in a manner which attenuate symptoms or cure the illness. Looks simple, but in practice is still far reachable goal for treating different kinds of tumors, retroviral infections, or neurodegenerative diseases. Along with this, relatively quick acquired resistance of pathogenic bacteria and viruses to existing marketed drugs made searching for the new drugs the never-ending race. In silico analysis of targets, analysis of interaction of targets with the small molecules that should modulate their physiological outcome, and search for small molecules that could favorably interact with the targets, is the one of the top-priority components of drug design framework. Pharmaceutical companies spend hundreds of millions of dollars per year for R&D projects. Within our group, three classes of promising lead compounds, that targeted human tumors, multidrug resistant bacteria (superbugs) and key enzyme responsible for Alzheimer disease, is developed so far. Within the actual project we aimed to further, and more efficiently use in silico techniques, which so far have a key importance for design of all three classes of molecules, as guidance for additional modification/improvement of structures, in order to obtain more potent and/or more selective compounds within all three examined classes.

Project should result with widening the pool of potentially healing substances (for the concept of chemical space, closely associated with previous statement see Nature 432(432) 823–865 (2004)), i.e. final results should facilitate curing life-threatening diseases or contribute to significant improvement of life quality in chronic illnesses: Non est vivere sed valere vita. Along with this, young researchers will be instructed/educated in using in silico techniques for rational design of bioactive molecules having desired mode of action.

Collaborations and Beneficiaries

Results of simulations developed during this project will be used for design of new compounds within our group (Department of Chemistry-IChTM, University of Belgrade and Faculty of Chemistry, University of Belgrade), as well as in collaborative work of our group with the School of Pharmacy, University of London, GB; and with the Chemistry Department, Laboratory of Organic Chemistry, University of Athens, and the National Hellenic Research Foundation, Athens, Greece.

Technical features and HP-SEE implementation

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Usage Example

• Primary programming language : Tobefilledin
• Parallel programming paradigm : Tobefilledin
• Main parallel code : Tobefilledin
• Pre/post processing code : Tobefilledin
• Application tools and libraries : Enumerate (comma separated)
• Number of cores required : Tobefilledin
• Minimum RAM/core required : Tobefilledin
• Storage space during a single run : Tobefilledin
• Long-term data storage : Tobefilledin

Publications and Presentations

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