Hit-to-lead is a process in drug discovery where a potential drug ‘hit’ or lead compound is identified from a large pool of chemical compounds or natural product extracts that have shown activity against a specific target. The goal of hit-to-lead optimization is to identify a lead compound that has sufficient potency, selectivity and drug-like properties. This process requires a multidisciplinar approach and often starts with high-throughput screening techniques.
Molecular Biophysics
Protein-protein, solute-solute, solute-lipid interactions
Cellular morphology and biomechanics
Cellular membrane penetration
Computational methods
Phage Display: used to screen large libraries of candidate molecules that act on/interact with a specific target. A gene encoding a protein/peptide of interest is inserted into a phage coat protein gene, causing the phage to “display” the protein on its outside. These displaying phages can then be screened against other proteins, peptides or DNA sequences, in order to detect interaction between the displayed protein/peptide and those other molecules. The in vivo phage display consists in the selection of phage libraries using biopannings in living animals. The phages circulate in the organism allowing the expressed molecules at the phage surface to bind directly to the specific target, organ or tissues.
This assay is often used to screen hit compounds for the treatment of neurological diseases, of CNS tumors and brain metastasis, and of infectious diseases (e.g. SARS-CoV-2, HIV, etc). It is used to evaluate drug candidate’s transport across the BBB and their effect on BBB integrity; to evaluate cytotoxicity and morphological alterations of BBB endothelial cells; to study drug transport mechanisms and to identify potential drug off-target effects in the brain.
In vitro Intestinal permeability evaluation
The study of the transport of drug candidates and other molecules across the intestinal epithelium is essential to predict their bioavailability in humans. Caco-2 (human colon adenocarcinoma cell line) cell culture model is widely used to that end as it closely resembles the intestinal epithelium in terms of morphology, function and expression of transport enzymes involved in drug absorption and metabolism. Thus, it can be used to predict oral drug absorption in humans, as well as to evaluate drug-drug interactions, toxicity and pharmacokinetics.
Outputs
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