6mrg: Difference between revisions

<StructureSection load='6mrg' size='340' side='right' caption='[[6mrg]], [[Resolution|resolution]] 2.77&Aring;' scene=''>

<table><tr><td colspan='2'>[[6mrg]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MRG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MRG FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JXV:(1R)-2-{[6-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrimidin-4-yl]amino}-1-phenylethan-1-ol'>JXV</scene></td></tr>

<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase Fatty acid amide hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.99 3.5.1.99] </span></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mrg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mrg OCA], [http://pdbe.org/6mrg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mrg RCSB], [http://www.ebi.ac.uk/pdbsum/6mrg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mrg ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/FAAH1_RAT FAAH1_RAT]] Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (By similarity).

Since a goal of most drug discovery projects in either academia or industry is to design molecules that selectively bind to the desired protein, determination of protein-ligand binding free energies is of utmost importance in computer aided drug design. With the help of significant improvements in computer power, enhanced sampling techniques and accuracy of force fields, FEP (free energy perturbation) is becoming an important tool to estimate binding free energies in many drug discovery projects both retrospectively and prospectively. We have evaluated the ability of Schrodinger's FEP+ to predict relative binding free energies of a congeneric series of noncovalent fatty acid amide hydrolase (FAAH) inhibitors using an in-house crystal structure. This study shows that although an impressively accurate correlation can be obtained with experimental IC50s considering small perturbations on the deeper side of the pocket, the same was not observed with small perturbations on the relatively more open-ended and solvent-accessible side of the pocket. To understand these observations, we thoroughly investigated several key factors including the sampling of asymmetrically substituted rings, different perturbation maps, impact of simultaneous perturbations at two different ends of the ligand, and selecting the perturbations in a "chemically sensible" way.

 

<div class="pdbe-citations 6mrg" style="background-color:#fffaf0;"></div>

== References ==

[[Category: Fatty acid amide hydrolase]]

[[Category: Mirzadegan, T]]

[[Category: Saha, A]]

[[Category: Seierstad, M]]

[[Category: Shih, A]]

[[Category: Hydrolase-inhibitor complex]]