Interactions found in the complexes between 6, 21 and the five 17β-HSD1 crystal structures used to build up the pharmacophore, respectively.

a<p>Distance (Å) between the heteroatoms for H-bonds (H) and between centroids or centroid and cation for π-interactions (π).</p

Synthesis of compounds 19–25.

<p>Reagents and conditions: (a) pyridine, 100°C, 20 h, for <b>19i</b>: <i>p</i>-methoxybenzoylchloride, for <b>21i</b>: <i>m</i>-methoxybenzoylchloride, for <b>22i</b>: <i>m</i>-methoxyphenylsulfochloride, for compound <b>23i</b>: <i>m</i>-methoxybenzoisocyanate, for <b>24i</b>: <i>m</i>-methoxybenzoisothiocyanate, for compound <b>25i</b>: <i>m</i>-methoxybenzylchloride; (b) for <b>19–21</b>, BF₃S(CH₃)₂, anhydrous CH₂Cl₂, rt, 20 h; for <b>22–25</b>, BBr₃, CH₂Cl₂, −78°C to rt, 20 h.</p

Pharmacophore derived complex between 17β-HSD1 (PDB-ID: 1equ) and compound 6 (dark orange).

<p>NADP⁺ (green), interacting residues (blue), potential interacting residues (black) and ribbon rendered tertiary structure of the active site are shown.</p

Steroidal ligands co-crystallized with 17β-HSD1.

<p>The five steroidal ligands cocrystalized with 17β-HSD1s that were used to build the pharmacophore model. Structural information was taken from the protein data bank(PDB-ID: 1a27, 1equ, 1dht, 1i5r, and 3hb5, respectively).</p

Discovery of Novel Bacterial RNA Polymerase Inhibitors: Pharmacophore-Based Virtual Screening and Hit Optimization

The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein–protein interaction (PPI) between σ⁷⁰ and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin

Rigidification strategy.

<p>Rigidification strategy.</p

Nonsteroidal 17β-HSD1 inhibitors published by our group.

<p>Nonsteroidal 17β-HSD1 inhibitors published by our group.</p

Pharmacophoric features exploited by 6 and 21.

<p>Six for compound <b>6</b> (showed in A) and five for compound <b>21</b> (showed in B).</p

Synthesis of compounds 6–18.

<p>Reagents and conditions: (a) 1) NaNO₂, H₃PO₄ (85%), −10°C, 20 min, 2) H₃PO₂, H₃PO₄ (85%), −10°C to rt, 20 h; (b) 1) nBuLi, anhydrous THF, −70°C to −20°C, 1 h, 2) for <b>6ii</b> and <b>12ii</b>: <i>m</i>-methoxybenzaldehyde, for <b>9ii</b>: <i>p</i>-methoxybenzaldehyde, for <b>15i</b>: <i>o</i>-methoxybenzoisocyanate, for <b>17i</b>: <i>m</i>-methoxybenzoisocyanate, anhydrous THF, −15°C, 90 min; (c) for <b>6i</b>, <b>12i</b> and <b>13i</b>, SIBX, anhydrous THF, 0°C to 60°C, 20 h; for <b>10</b> and <b>11i</b>: TMSiCl, NaI, CH₃CN, reflux, 20 h; (d) for <b>6–9</b> and <b>15–18</b>: BF₃S(CH₃)₂, anhydrous CH₂Cl₂, rt, 20 h; for compounds <b>11–14</b>, pyridinium hydrochloride, 220°C, 4 h.</p

Pharmacophore model.

<p>The pharmacophoric features derived from the ligands are rendered as dotted spheres and are color-coded: dark orange for aromatic ring and aromatic ring projection (<b>HY1</b> and <b>HY5</b>), green for hydrophobic regions (<b>HY2-HY4</b>) and magenta for acceptor and donor atom features (<b>AD1-AD3</b> and <b>D4</b>). The identified aromatic ring projection <b>HY6</b> as well as the donor projection feature <b>D7</b> is not exploited by steroidal inhibitors. The protein-derived acceptor or donor features (<b>A1a</b>, <b>D1b</b>, <b>AD2a</b>, <b>AD2b</b>, <b>A3a</b>, <b>D4a</b>, <b>D4b</b>, <b>AD5a</b>, <b>AD5b</b>, <b>D6a</b> and <b>A6b</b>) and the aromatic ring projection <b>P5</b> are depicted as yellow, meshed spheres.</p