title: Structural determination of three different series of compounds as Hsp90 inhibitors using 3D-QSAR modeling, molecular docking and molecular dynamics methods.
abstract: Hsp90 is involved in correcting, folding, maturation and activation of a diverse array of client proteins; it has also been implicated in the treatment of cancer in recent years. In this work, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular docking and molecular dynamics were performed on three different series of Hsp90 inhibitors to build 3D-QSAR models, which were based on the ligand-based or receptor-based methods. The optimum 3D-QSAR models exhibited reasonable statistical characteristics with averaging internal q(2) > 0.60 and external r(2) (pred) > 0.66 for Benzamide tetrahydro-4H-carbazol-4-one analogs (BT), AT13387 derivatives (AT) and Dihydroxylphenyl amides (DA). The results revealed that steric effects contributed the most to the BT model, whereas H-bonding was more important to AT, and electrostatic, hydrophobic, H-bond donor almost contributed equally to the DA model. The docking analysis showed that Asp93, Tyr139 and Thr184 in Hsp90 are important for the three series of inhibitors. Molecular dynamics simulation (MD) further indicated that the conformation derived from docking is basically consistent with the average structure extracted from MD simulation. These results not only lead to a better understanding of interactions between these inhibitors and Hsp90 receptor but also provide useful information for the design of new inhibitors with a specific activity.
authors.affiliation: College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China; E-Mails: ljl2003ljl@126.com (J.L.); yu100288@163.com (F.W.).
authors.forename: Jianling
authors.initials: J
authors.lastname: Liu
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ma
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D001549:Benzamides; D002227:Carbazoles; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone