Molecular dynamics simulations as a guide for modulating small molecule aggregation.

Small colloidally aggregating molecules (SCAMs) can be problematic for biological assays in drug discovery campaigns. However, the self-associating properties of SCAMs have potential applications in drug delivery and analytical biochemistry. Consequently, the ability to predict the aggregation propensity of a small organic molecule is of considerable interest.

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates biological signals to control various complicated cellular functions. It plays a crucial role in environmental sensing and xenobiotic metabolism. Dysregulation of AhR is associated with health concerns, including cancer and immune system disorders.

Applications of Molecular Dynamics Simulations in Drug Discovery.

In the current drug development process, molecular dynamics (MD) simulations have proven to be very useful. This chapter provides an overview of the current applications of MD simulations in drug discovery, from detecting protein druggable sites and validating drug docking outcomes to exploring protein conformations and investigating the influence of mutations on its structure and functions. In addition, this chapter emphasizes various strategies to improve the conformational sampling efficiency in molecular dynamics simulations.

Structural analysis of hERG channel blockers and the implications for drug design.

The repolarizing current (I) produced by the hERG potassium channel forms a major component of the cardiac action potential and blocking this current by small molecule drugs can lead to life-threatening cardiotoxicity. Understanding the mechanisms of drug-mediated hERG inhibition is essential to develop a second generation of safe drugs, with minimal cardiotoxic effects. Although various computational tools and drug design guidelines have been developed to avoid binding of drugs to the hERG pore domain, there are many other aspects that are still open for investigation.

Investigation of New Inhibitors of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) by Virtual Screening with Antibacterial Assessment.

Background: Considering the interesting role in the peptidoglycan biosynthesis pathway, the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase is an attractive target to develop new antibacterial agents. It catalyzes the first key step of this pathway and its inhibition leads to bacterial cell death. Fosfomycin is known as the natural inhibitor of MurA.

Anti-inflammatory drug approach: Synthesis and biological evaluation of novel pyrazolo[3,4-d]pyrimidine compounds.

In this study, the acid chlorides of pyrazolo[3,4-d]pyrimidine compounds were prepared and reacted with a number of nucleophiles. The novel compounds were experimentally tested via enzyme assay and they showed cyclooxygenase-2 inhibition activity in the middle micro molar range (4b had a COX-1 IC of 26 µM and a COX-2 IC of 34 µM, 3b had a COX-1 IC of 19 µM and a COX-2 IC of 31 µM, 3a had a COX-2 IC of 42 µM). These compounds were analyzed via docking and were predicted to interact with some of the COX-2 key residues.