BIOSOL

Solvent effects on physico-chemical properties of bioactive compounds: combination of theory with experiments

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 Obiettivo del progetto (Objective)

'Recent developments in combinatorial chemistry, high throughput screening, and robotics led to a large number of compounds with potential biological activity. The vast and ever increasing number of possible lead molecules requires prioritizing the most promising compounds. Physicochemical properties of the drugs in solutions determine their pharmacodynamics and pharmacokinetcs and, therefore, are of key importance in the further development process. We propose a multidisciplinary project that includes correlated experimental and theoretical efforts to understand the molecular mechanisms of structural changes of biomolecules and thermodynamics of biomolecular solvation. The Max Planck group has recently proposed new modeling approaches based on the combinations of several methods of computational chemistry as the improved integral equations theory, molecular mechanics and the density functional theory. This approach allows one to predict the physicochemical properties of biomolecules in solution with high accuracy but with low computational cost. We believe that the combination of the novel modeling methods with direct cutting-edge experiments made by other participants should provide new insights on the intriguing problems of biomolecule solvation such as: 1. How solvent properties (type of solvent, temperature, pH, ionic strength, cosolvents, etc) affect physico-chemical properties of bioactive molecular compounds? 2. What are the molecular mechanisms of different solubility pathways for bioactive compounds: in aqueous solutions and what is the role of polimorphism on the solubility pathways? 3. What are the effects of ions (concentration and type of ions present in the solution) and pH on the solvation properties of bioactive compounds? 4. What are the basic molecular principles of solubilisation of ionised and non-ionised compounds in supercritical fluids? 5. Can we still operate with such terms as solvation shell and solvated complex in supercritical solvents?'

Introduzione (Teaser)

Combining combinatorial chemistry, high-throughput screening (HTS) and robotics led to the discovery of several promising bioactive compounds with varying physicochemical properties in solutions. Biomolecular solvation is of particular relevance as drugs need to be soluble in biological fluids in order to be therapeutically effective in vivo.

Descrizione progetto (Article)

The EU-funded multidisciplinary BIOSOL project will combine low-cost computational chemistry with mathematical modelling, molecular mechanics and density functional theory to optimise biomolecular solvation. BIOSOL researchers will enhance the solubility of bioactive compounds through polymorphism, pH control and the use of co-solvents. Polymorphism is the ability of a biomolecule to exist in different solid forms based on crystal structure and other properties.

BIOSOL members studied the solvation thermodynamics of promising bioactive molecules by combining experimental and theoretical methods with computational chemistry. They optimised their computational model by developing more efficient methods to solve the integral equations used in the model.

Supercritical fluids technology was used to selectively crystallise specific polymorphs of bioactive molecules by varying solvent parameters. Supercritical is the state in which there is no distinct liquid and gas phase in a substance at certain temperature and pressure conditions. The characterisation of biomolecule crystal structure dependence on solvent composition is currently ongoing.

Successful BIOSOL outcomes should provide novel insight into the effects of solvent properties and polymorphism on compounds' solubility. Project outcomes should also increase the bioavailability of several bioactive compounds whose application in therapy has been hampered by their insolubility in biological fluids.