swoil n; 'seal oil'

seal nHe told me to give her / A cup of old swoil.PRINTED ITEM JUL 1 1988G.M.Story WKUsed I and SupUsed I3Used Isile,soil,swale,swile,swoil(e),bay,harbour,harp,hood,old,square flipper,square a,young,bedlamer,dotard,ragged-jacket,saddleback,turner,white-coat,pelt n,sculp n;~bait/bat/cat/catcher/dart/fat/finger/hunt(er)/gun/hand/heaMore collocations:~hunting/shot/skin(er)/soap/twine/vat/bird/penis/worm/frame/oil/pan/pass/patch;~fish/er(y)/ing;dog1;pup;cock,cod worm;snub1;blow hole;bobbing~;sealer1;fish kille

Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206

<div><p>The AKT signaling pathway has been identified as an important target for cancer therapy. Among small-molecule inhibitors of AKT that have shown tremendous potential in inhibiting cancer, MK-2206 is a highly potent, selective and orally active allosteric inhibitor. Promising preclinical anticancer results have led to entry of MK-2206 into Phase I/II clinical trials. Despite such importance, the exact binding mechanism and the molecular interactions of MK-2206 with human AKT are not available. The current study investigated the exact binding mode and the molecular interactions of MK-2206 with human AKT isoforms using molecular docking and (un)binding simulation analyses. The study also involved the docking analyses of the structural analogs of MK-2206 to AKT1 and proposed one as better inhibitor. The Dock was used for docking simulations of MK-2206 into the allosteric site of AKT isoforms. The Ligplot+ was used for analyses of polar and hydrophobic interactions between AKT isoforms and the ligands. The MoMa-LigPath web server was used to simulate the ligand (un)binding from the binding site to the surface of the protein. In the docking and (un)binding simulation analyses of MK-2206 with human AKT1, the Trp-80 was the key residue and showed highest decrease in the solvent accessibility, highest number of hydrophobic interactions, and the most consistent involvement in all (un)binding simulation phases. The number of molecular interactions identified and calculated binding energies and dissociation constants from the co-complex structures of these isoforms, clearly explained the varying affinity of MK-2206 towards these isoforms. The (un)binding simulation analyses identified various additional residues which despite being away from the binding site, play important role in initial binding of the ligand. Thus, the docking and (un)binding simulation analyses of MK-2206 with AKT isoforms and its structure analogs will provide a suitable model for studying drug-protein interaction and will help in designing better drugs.</p></div

(Un)binding simulation analyses of MK-2206 binding to the allosteric site of human AKT1.

<p>Panels A–I: The (un)binding simulation phases of MK-2206; ‘A’ denotes farthest phase from the binding site, ‘H’ - the closest to the binding site, and ‘I’ - the binding site phase. The hydrogen bonds are shown as green-dashed lines with indicated bond length and the residues involved in hydrophobic interactions are shown as red arcs. The residues which are common to the last phase (F) are encircled.</p

Comparison of MK-2206 binding and interacting residues of all three isoforms of AKT.

<p>Only one residue Asn-53 was shared among interacting residues of AKT1 and AKT2, and shown as encircled in green. Three position-equivalent-residues (residues of different isoforms falling at same column position in the isoform alignment) were shared among interacting residues of AKT2 and AKT3, and shown as encircled in red.</p

Procheck analyses for quality of structure models of AKT2 and AKT3 with the common template.

<p>Ramachandran plot analyses showing the percentage of residues lying in each of the four different regions. In disallowed region, the number of residues is also given in parantheses with percentage. The number of labeled residues in all Ramachandrans and Chi1–Chi2 are also given in the table.</p><p>Procheck analyses for quality of structure models of AKT2 and AKT3 with the common template.</p

Structural analogs of MK-2206 can be derived by varying R1 and R2 group on common scaffold according to devised rules on visual analyses.

<p>For the drug MK-2206, R₁ is 1-amino cyclo-butyl group and R₂ is ketonic oxygen.</p

Ramachandran plot showing the residues as square dots lying in the four different regions, most favorable, additional allowed, generously allowed, and disallowed regions.

<p>Ramachandran plot showing the residues as square dots lying in the four different regions, most favorable, additional allowed, generously allowed, and disallowed regions.</p

The binding strength of MK-2206 to the three AKT isoforms given by various scores are listed in the table.

<p>The binding strength of MK-2206 to the three AKT isoforms given by various scores are listed in the table.</p

Comparative binding analyses of MK-2206 and inhibitor VIII.

<p>Panels A–B: The binding of MK-2206 and inhibitor VIII are displayed. The hydrogen bond is shown as green-dashed line with indicated bond length and the residues involved in hydrophobic interactions are shown as red arcs. The interacting residues which are common for both the ligands are encircled. Panel C: The exact orientation of binding for both the ligands in the binding site of the protein is shown. Panel D: Schematic structure of MK-2206 and inhibitor VIII are shown. The three ring moieties of both the molecules are encircled.</p

Comparative binding analyses of MK-2206 and its selected analog.

<p>Panels A–B: Schematic structure of MK-2206 and its analog are shown. The only difference between the compounds is change in R₂ group, shown in red on black compound-scaffold. Panel C–D: The binding of MK-2206 and its selected analog are displayed. The residues involved in hydrophobic interactions are shown as red arcs. The interacting residues which are common for both the ligands are encircled.</p