Determination of Binding Conformation of Drugs to Human Serum Albumin by Molecular Dynamics Calculations and Transferred Nuclear Overhauser Effect Measurements

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The binding conformations of oxyphenbutazone (OXY), Nepsilon-dansyl-L-lysine (DNS-LYS), and furosemide (FU) to human serum albumin (HSA) have been investigated by molecular dynamics (MD) calculation and transferred nuclear Overhauser effect (TRNOE) measurements. We have combined distance information obtained from Conformational Analyzer with Molecular Dynamics And Sampling (CAMDAS) calculation and experimental NOE spectroscopy measurements to perform an extraction of a "binding conformer" for drugs binding to the HSA molecular site I.We have obtained for the site I binding drugs OXY,DNS-LYS,and FU,1,17, and 5 "selected conformer" respectively. For OXY,one selected conformer (conf9) was obtained. The basic binding conformer structure of conf9 was taken as a "template" to choose binding conformers for DNS-LYS and FU.By fitting the 17 DNS-LYS and 5 FU conformers to the "template" using three dimensional computer graphics, we can efficiently obtaine one binding conformer respectively for DNS-LYS (conf144) and FU (conf21). Results from fitting the binding conformers of these three drug suggests that a feature of the steric structure of HSA biding drugs is that comparatively hydrophobic side chains, such as butyl group, lysine group or furan ring, cover hydrophobic portions such as phenyl or dansyl group, or that they take a neighboring compact structure. This method of combining MD calculation and NOE information suggested to an extremely effective method for obtaining steric conformation for drugs bound to HSA.