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/6À31G(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 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
The UPMANILA The Perspectives of Pharmacy, Medical and Nursing Students Towards Interdisciplinary Approach in Medication Management Sherilyn E. Cabarles, Ruffa C.D. Castro, Lynette Bernardine Kawi, Roderick L. Salenga The objective of the study was to determine the understanding by pharmacy, medical, and nursing students of Interdisciplinary Approach in medication management. Pharm
Lei n.º 1 /2002 de 7 de Agosto Publicação dos actos A Constituição da República deixa ao legislador ordinário a definição de diversas matérias relacionadas com os actos normativos que compõem o ordenamento jurídico da República. Considerando que a lei deve definir, o mais brevemente possível, os tipos de diplomas existentes e aprovar os respectivos formulários bem como as