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Docking and 3D-QSAR studies on isatin sulfonamide analogues as caspase-3 inhibitors.

ABSTRACT: To provide insight of their inhibition mechanism and facilitate the design of more potent ligands, a series of 59 isatin sulfonamide analogues were docked to the X-ray structure of caspase-3, one of the important cysteine aspartyl-specific execution proteases in apoptosis, and their binding conformations were analyzed by 3D-QSAR studies. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies suggest that both steric and electrostatic interactions contribute to the compounds' binding affinity, with the major contribution arising from hydrophobic interactions. The models show excellent correlation and high predictive power even evaluated by the most stringent criteria for a QSAR model. The results of this work demonstrate that structure-based design methods (such as docking) cultivate the development of reliable QSAR models; they also illustrate the utility of this procedure in design of new potent caspase-3 ligands.

SUBMITTER: Wang Q

PROVIDER: S-EPMC2767110 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Docking and 3D-QSAR studies on isatin sulfonamide analogues as caspase-3 inhibitors.

Wang Qi Q Mach Robert H RH Reichert David E DE

Journal of chemical information and modeling 20090801 8

To provide insight of their inhibition mechanism and facilitate the design of more potent ligands, a series of 59 isatin sulfonamide analogues were docked to the X-ray structure of caspase-3, one of the important cysteine aspartyl-specific execution proteases in apoptosis, and their binding conformations were analyzed by 3D-QSAR studies. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies suggest that both steric and electrostatic int ...[more]

PMID: 19610597

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Project description:A strategy in the discovery of anti-tuberculosis (anti-TB) drug involves targeting the enzymes involved in the biosynthesis of Mycobacterium tuberculosis' (Mtb) cell wall. One of these enzymes is Galactofuranosyltransferase 2 (GlfT2) that catalyzes the elongation of the galactan chain of Mtb cell wall. Studies targeting GlfT2 have so far produced compounds showing minimal inhibitory activity. With the current challenge of designing potential GlfT2 inhibitors with high inhibition activity, computational methods such as molecular docking, receptor-ligand mapping, molecular dynamics, and Three-Dimensional-Quantitative Structure-Activity Relationship (3D-QSAR) were utilized to deduce the interactions of the reported compounds with the target enzyme and enabling the design of more potent GlfT2 inhibitors. Molecular docking studies showed that the synthesized compounds have binding energy values between -3.00 to -6.00 kcal mol-1. Two compounds, #27 and #31, have registered binding energy values of -8.32 ± 0.01, and -8.08 ± 0.01 kcal mol-1, respectively. These compounds were synthesized as UDP-Galactopyranose mutase (UGM) inhibitors and could possibly inhibit GlfT2. Interestingly, the analogs of the known disaccharide substrate, compounds #1-4, have binding energy range of -10.00 to -19.00 kcal mol-1. The synthesized and newly designed compounds were subjected to 3D-QSAR to further design compounds with effective interaction within the active site. Results showed improved binding energy from -6.00 to -8.00 kcal mol-1. A significant increase on the binding affinity was observed when modifying the aglycon part instead of the sugar moiety. Furthermore, these top hit compounds were subjected to in silico ADMETox evaluation. Compounds #31, #70, #71, #72, and #73 were found to pass the ADME evaluation and throughout the screening, only compound #31 passed the predicted toxicity evaluation. This work could pave the way in the design and synthesis of GlfT2 inhibitors through computer-aided drug design and can be used as an initial approach in identifying potential novel GlfT2 inhibitors with promising activity and low toxicity.

Dataset Information

Docking and 3D-QSAR studies on isatin sulfonamide analogues as caspase-3 inhibitors.

Publications

Docking and 3D-QSAR studies on isatin sulfonamide analogues as caspase-3 inhibitors.

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