033-chem-remko 153.155

Comenius University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Bratislava, Slovakia Within this project I used computer facilities of SARA Amsterdam for doing  Theoretical study of structure, pKa, lipophilicity, solubility, absorption and polar surface area of some centrally acting antihypertensives  Theoretical study of structure and properties of biologically active glycosami- noglycans in solution and their complexes with proteins The subproject ``Antihypertensives'' was finished during my study stay at the Free University Amsterdam. The results of calculations at SARA were included into our common publication [1] (submitted for publication to the Journal ``Bioorganic & The subproject ` Glycosaminoglycans' was not finished because of the problems to get more budgets. As the calculations performed within this subproject represent already a substantial amount of ``invested CPU hours'' we decided to apply for extra budget in order to continue the calculations.
All calculations at the SARA were performed with the Amsterdam Density  Within the subproject ``Antihypertensives'' we carried out a large-scale calcula- tions of structure and properties of 13 drugs. Brief summary of this work is as Theoretical study of structure,pKa,lipophilicity,solubility,ab- sorption and polar surface area of some centrally acting antihy- The methods of theoretical chemistry have been used to elucidate the molecular properties of the substituted imidazoline and oxazoline structures, a class of potent agonists and antagonists of imidazoline receptors. The geometries of various tautomers and isomers of 2-[2,6-dichlorophenyl)imino]imidazolidine (clonidine), 1-(N-dicyclopro- phylmethyl)amino-2-oxazoline (rilmenidine), 4-chloro-N-(4,5-dihydro-1H-imidazol-2yl)-6- methoxy-2-methyl-5-pyrimidinamine (moxonidine), N-(dicycloprophylmethyl)-4,5-dihy- dro-1H-pyrrol-2-amine (aminopyrroline), N-dicycloprophylmethyl)-4,5-dihydrothiazol-2- amine (aminothiazoline), 4,5-dihydro-2-(2-methoxyphenyl)-1H-imidazole (compound_9), 4,5-dihydro-2-(3-methylthiophen-2-yl)-1H-imidazole (compound_10), N-(2-chloro-4-iodo- phenyl)-4,5-dihydro-5-methyl-3H-pyrrol-2-amine (LNP_911), N-amidino-3,5-diamino-6- chloropyrazine-carboxamide (amiloride), 2-(1,4-benzodioxan-2-yl)-2-imidazoline (idazox- an), (Æ)-2-(2-ethyl-2,3-dihydro-2-benzofuranyl)-2-imidazoline (efaroxan), (4-aminobutyl)- guaninine (agmatine) and 1-methyl-9H-pyrido[3,4-b]indole (harmane) have been studied using the Becke3LYP/6À31‡G(d,p) and BP86/TZ2P DFT methods. The optimized geometries indicate that these molecules show a distinctly nonplanar configuration of the imidazoline and oxazoline moieties. In the gas phase, rilmenidine and aminothiazoline exist in two forms (amino and imino), the amino tautomers are more stable by about 6 kJ/mol. The calculations showed, in agreement with experiments, that clonidine, moxonidine and LNP_911 exist in more stable imino tautomer. The tautomer containing the amino group is by about 30 kJ/mol less stable. Computations that include the effect of solvation, indicated that also in water solution the relative stability order of individual tautomers (amino and imino forms) is preserved. The computed pKa values varied between 6.7 and 9.0 and correlate well with the available experimental pKa's found in the literature. Amongst the clinically useful antihyperten- sives moxonidine exhibits the lowest basicity in water solution. At pH ˆ 7.4 only about 50% of this drug exists in ionised form. The available experimental partition coeffi- cients of compounds investigated are best reproduced by the CLOGP method. The computed partition coefficients varied between À1.80 (agmatine) and 5.35 (LNP_911) (CLOGP). Clonidine, moxonidine and rilmenidine are moderately lipophilic com- pounds with lipophilicities between these two extreme values. The computed solubilities (about 0.1 À 4 g/L) show that the imidazoline and oxazoline derivatives studied have very low water solubility. The analysis of molecular descriptors defined by Lipinski has been shown that most of the compounds studied obey ``Rule of Five''.
Amiloride and agmatine ``outlets'' exhibit also the lowest absorption. Therefore, in the early stages of the design of ligands acting on imidazoline binding sites, it is becoming more important to determine the pKa, lipophilicity, water solubility, polar surface area, MOLECULARMODELING OF PHARMACOLOGICALLY ACTIVE SUBSTANCES absorption and other physicochemical properties associated with a drug, before synthetic work is undertaken, with the aim of avoiding the synthesis of compounds that are predicted to have poor biopharmaceutical characteristics.
 The subproject ``Glycosaminoglycans'' contains accurate determination of 3D structure and properties of oligosaccharides (penta ±, hexasaccharides) using sophisticated quantum chemical methods. For effective conduction of quantum chemical calculations for such large systems we need large computer resources, which are currently not available at university level calculations. The SARA computer facilities were very helpful in this sense.
The calculations performed at SARA Amsterdam represent important contribu- tion to our common research and promoted my collaboration with the colleagues at the Acknowledgements. This work was carried out under the HPC-EUROPA project (RII3-CT-2003-506079), with the support of the European Community ± Research Infrastructure Action under the FP6 ` Structuring the European Research Area'' [1] M. REMKO, M. SWART and F. M. BICKELHAUPT, Bioorg. & Med. Chem. (2005) submitted for

Source: http://www.hpc-europa.eu/files/SSCinEurope/CD2005/content/026-Chemistry.pdf