Antiproliferativna aktivnost glutarimidnih derivata iz baze podataka Nacionalnog instituta za rak, SAD - 3D odnos strukture i aktivnosti nezavisan od poravnavanja molekula

Alignment-free, three dimensional structure-activity relationships (3D QSAR) of the antiproliferative potency of twenty-two glutarimide-containing compounds, taken from National Cancer Institute Developmental therapeutics Program database, toward eight representative human tumour cell lines are reported. The descriptors used in the QSAR study were derived from GRID molecular interaction fields. The obtained models readily detect structural motifs positively or negatively correlated with the potency of the studied compounds toward each cell line. In this way, the pharmacophoric pattern required for high potency of compounds is reported. This pattern can serve as guidance for the design and syntheses of novel congeners, planned to be tested toward human tumour cell lines.U tekstu je opisan odnos strukture i antiproliferativne aktivnosti 22 glutarimidna derivata prema osam reprezentativnih linija humanih tumora. Podaci o strukturi jedinjenja i njihovoj aktivnosti su preuzeti iz baze podataka Nacionalnog Instituta za rak, SAD. Deskriptori, nezavisni od poravnavanja molekula (GRIND-2), korišćeni u proučavanju odnosa strukture i aktivnosti su dobijeni upotrebom programa GRID. Modeli jasno prikazuju strukturne elemente jedinjenja koji se pozitivno ili negativno korelišu sa biološkom aktivnošću. Farmakoforna slika dobijena iz modela će biti korišćena za planiranje novih analoga koji sadrže glutarimidni prsten i za koje se očekuje da će pokazati značajnu antiproliferativnu aktivnost

Importance of inter-residue interactions in ligand-receptor binding

In the present study, the role of inter-residue interactions in ligand binding and the ligand-receptor interactions were examined. Computational chemistry methods of ligand docking and molecular dynamics simulations were used to study the binding of beta-funaltrexamine (beta-FNA) and N-methyl-beta-funaltrexamine (N-methyl-beta-FNA) to mu- and kappa-opioid receptors and to the mu-receptor with Lys303(6.58) Glu mutation. It was found that inter-residue interactions Lys233(5.39)-Glu303(6.58) in the mutant receptor and Lys227(5.39) Asp223(5.35) in the.-receptor are more likely to prevent covalent bond formation between beta-FNA and the receptor than the ligand-receptor interactions. This emphasizes the importance of inter-residue interactions in ligand binding as well as the effects of point-mutations. (C) 2016 Institute of Chemistry, Slovak Academy of Science

Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in an attempt to develop highly selective mu-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the mu-opioid receptor model, in order to test the hypothesis that the hydrophobic pocket accommodates alkyl groups at position 3 of the fentanyl skeleton, is described. The stereoisomers of the following compounds were studied: cis- and trans-3-methylfentanyl. 3.3-dimethylfentanyl. cis- and trans-3-ethylfentanyl, cis- and trans-3-propylfentanyl, cis-3-isopropylfentanyl and cis-3-benzylfentanyl. The optimal position and orientation of these fentanyl analogs in the binding pocket of the mu-receptor, explaining their enantiospecific potency, were determined. It was found that the 3-alkyl group of cis-3R,4S and trans-3S,4S stereoisomers of all the active compounds occupies the hydrophobic pocket between TM5, TM6 and TM7, made LIP of the amino acids Trp318 (TM7), Ile322 (TM7), 1001 (TM6) and Phe237 (TM5). However, the fact that this hydrophobic pocket can also accommodate the bulky 3-alkyl substituents of the two inactive Compounds: cis-3-isopropylfentanyl, and cis-3-benzylfentanyl, indicates that this hydrophobic pocket in the employed receptor model is probably too large

Modeling the ligand specific μ- and δ-opioid receptor conformations

An automated docking procedure was applied to study the binding of a series of mu- and delta-selective ligands to ligand-specific mu- and delta-opioid receptor models. Short-time molecular dynamic simulations were used to obtain ligand-specific mu- and delta-opioid receptors from arbitrarily chosen models of the active form of these receptors. The quality of receptor model depended on the molecular volume of the ligand in the receptor-ligand complex used in the molecular dynamic simulations. Within a series of ligands of similar size (volume), the results of ligand docking to the obtained ligand-specific receptor conformation were in agreement with point mutation studies. The correlation of the calculated and the experimentally determined binding energies was improved in relation to the initial receptor conformation.Računska metoda automatizovanog dokiranja primenjena je na vezivanje serije liganada, specifičnih za µ- i δ-receptore, za modele ovih receptora. Kratkotrajna molekulsko dinamička simulacija je korišćena za dobijanje konformacija ovih receptora koje su specifične za pojedine ligande, polazeći od slučajno izabranog modela aktiviranog receptora. Kvalitet ovako dobijenog modela receptora zavisi od molekulske zapremine liganda u ligand-receptor kompleksu korišćenog u molekulsko-dinamičkoj simulaciji. Za seriju liganda slične zapremine rezultati dokiranja su u skladu sa eksperimentalnim rezltatima mutacija aminokiselina u receptoru. Korelacija izračunatih i merenih energija vezivanja je poboljšana u odnosu na rezultate dobijene sa polaznom konformacijom receptora