Validation of molecular docking programs for virtual screening against dihydropteroate synthase

Dihydropteroate synthase (DHPS) is the target of the sulfonamide class of antibiotics and has been a validated antibacterial drug target for nearly 70 years. The sulfonamides target the p-aminobenzoic acid (pABA) binding site of DHPS and interfere with folate biosynthesis and ultimately prevent bacterial replication. However, widespread bacterial resistance to these drugs has severely limited … Continued

Template CoMFA: The 3D-QSAR Grail?

Template CoMFA, a novel alignment methodology for training or test set structures in 3D-QSAR, is introduced. Its two most significant advantages are its complete automation and its ability to derive a single combined model from multiple structural series affecting a biological target. Its only two inputs are one or more “template” structures having 3D coordinates … Continued

Design of Novel FLT-3 Inhibitors Based on Dual-layer 3D-QSAR Model and Fragment-based Compounds In Silico

FMS-like tyrosine kinase 3 (FLT-3) is strongly correlated with acute myeloid leukemia, but no FLT-3-inhibitor cocomplex structure is available to assist the design of therapeutic inhibitors. Hence, we propose a dual-layer 3D-QSAR model for FLT-3 that integrates the pharmacophore, CoMFA, and CoMSIA. We then coupled the model with the fragment-based design strategy to identify novel … Continued

Binding Conformation of 2-oxoamide Inhibitors to Group IVA Cytosolic Phospholipase A2 Determined by Molecular Docking Combined with Molecular Dynamics

The Group IVA cytosolic phospholipase A2 (GIVA cPLA2) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA2 inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA2 active site through a combination of … Continued

Capturing Structure-activity Relationships from Chemogenomic Spaces

Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for … Continued

Molecular Docking and 3D-QSAR CoMFA Studies on Indole Inhibitors of GIIA Secreted Phospholipase A(2)

Automated docking allowing a “”protein-based”” alignment was performed on a set of indole inhibitors of the GIIA secreted phospholipase A(2) (GIIA sPLA(2)). A correlation between the binding scores and the experimental inhibitory activity was observed (r2 = 0.666, N = 34). All the indole inhibitors were docked in the active site of the GIIA sPLA(2) … Continued

Discovery of New Inhibitors of Schistosoma Mansoni PNP by Pharmacophore-based Virtual Screening

Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma mansoni , one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the … Continued

Comparative Evaluation of 3D Virtual Ligand Screening Methods: Impact of the Molecular Alignment on Enrichment

In the early stage of drug discovery programs, when the structure of a complex involving a target and a small molecule is available, structure-based virtual ligand screening methods are generally preferred. However, ligand-based strategies like shape-similarity search methods can also be applied. Shape-similarity search methods consist in exploring a pseudo-binding-site derived from the known small … Continued

Scoring Ensembles of Docked Protein: Ligand Interactions for Virtual Lead Optimization

Ensembles of protein structures to simulate protein flexibility are widely used throughout several applications including virtual lead optimization where they have been shown to improve ligand ranking. Yet, there is no established convention for weighting individual scores generated from ensemble members. To investigate the best method for weighting ensemble scores for proper ligand ranking, a … Continued

Small-molecule Interferon Inducers: Toward the Comprehension of the Molecular Determinants Through Ligand-based Approaches

Hepatitis C is becoming an increasingly common cause of mortality especially in the HIV-coinfected group. Due to the efficacy of interferon (IFN) based therapy in the treatment of hepatitis C, various compounds possessing IFN-inducing activity have been hitherto reported. In the present study, we describe how steric, electrostatic, hydrophobic, and hydrogen-bonding interactions might influence the … Continued

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