Molecular Design of Anticancer Drug Leads Based on Three-Dimensional Quantitative Structure–Activity Relationship

Abstract

Heat shock protein 90 (Hsp90) takes part in the developments of several cancers. Novobiocin, a typically C-terminal inhibitor for Hsp90, will probably used as an important anticancer drug in the future. In this work, we explored the valuable information and designed new novobiocin derivatives based on a three-dimensional quantitative structure-activity relationship (3D QSAR). The comparative molecular field analysis and comparative molecular similarity indices analysis models with high predictive capability were established, and their reliabilities are supported by the statistical parameters. Based on the several important influence factors obtained from these models, six new novobiocin derivatives with higher inhibitory activities were designed and confirmed by the molecular simulation with our models, which provide the potential anticancer drug leads for further research.

Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety

“…The 3D structures of all molecules were built using the ‘Sketch Molecule’ function in Sybyl. Initial optimisation of the structures was carried out using the Gasteiger–Hückel charge, Tripos force field and Powell conjugate gradient algorithm with a convergence criterion of 0.005 kcal mol −1 Å −1 . The 3D structures of the 30 molecules were aligned on a common template molecule with 8f , with the best protective activity against TMV, for the CoMFA and CoMSIA modelling study.…”

Novobiocin analogues with second-generation noviose surrogates

“…21 During the course of studies aimed at the modification of these amines, Huang and coworkers developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model that suggested modifications to the amine may improve anti-proliferative activity. 23 Consequently, second generation amino-analogues were designed, synthesized and evaluated against two breast cancer cell lines.…”

“…In addition, Huang and co-workers suggested in their 3D-QSAR study that steric bulk N -substitution of NA-2 could lead to increased anti-proliferative activity. 23 Therefore, analogues containing various linear and branched N -substitutions were pursued in an effort to maintain both the hydrophobicity and the H-bond donor properties. As shown in Scheme 3, compound 23 was treated with primary and secondary amines ( 34a – 34o ) to produce the corresponding secondary and tertiary amine derivatives containing various linear or branched chains ( 35a – 35k ).…”

Synthesis, Antiviral Bioactivity of Novel 4-Thioquinazoline Derivatives Containing Chalcone Moiety

“…In order to analyze the SAR base on the protection activity against TMV, the CoMFA of 3D-QSAR model [28] with a total of twenty-one target compounds were developed by using Sybyl 7.3 software [29] from Tripos Inc. (St. Louis, MO, USA). Predicted pEC50 [30] values of compounds in both the training and testing sets were presented together with their actual pEC50 values in Table 2, and correlations between predicted and actual pEC50 in CoMFA model were presented in Figure 1.…”

“…The 3D structures of all molecules were built using the "Sketch Molecule" function in Sybyl. Initial optimization of the structures were carried out using the Gasteiger-Hückel charge, Tripos force field, and Powell conjugate gradient algorithm with a convergence criterion of 0.005 kcal/mol·Å [28]. The 3D structures of the 21 molecules were aligned on a common template molecule with M 6 for the CoMFA modeling study.…”