 | 
|
|
 |  |
|
 |
||
(Person in charge: G. MOROY)
Hits to lead (1 ECTS)
(Persons in charge: : O. TABOUREAU)
Program :
Several experimental approaches and rational in silico design methods can be used to transform a "hit" into a "lead" (X-ray diffraction, NMR, medicinal chemistry, SAR, QSAR, rescoring, molecular simulation, ligand-based, fragment-based methods...).
Several examples of optimization will be discussed with applications in infectious diseases, cancer, cardiovascular diseases and the reproductive system.
The aim of screening is to identify molecules with biological activity of therapeutic interest with respect to a therapeutic target. High throughput, in silico or in vitro, allows the testing of several thousand molecules per week. Pharmacological screening is the first step in the drug discovery process. The molecules identified during the initial screening phase (hits) are far from being drugs yet. Their binding to their target is still too weak, so they will have to be optimized (leads). Thanks to subtle and progressive transformations of the structure of the hit, the medicinal chemist and the drug designer will allow it to bind more efficiently to its target. However, this increase in affinity alone will not be enough to make the key a drug candidate. Before being evaluated in animal efficacy models and then in humans, the product will have to satisfy several other constraints: a) specificity, b) adequate bioavailability, c) appropriate pharmacokinetic properties, d) absence of toxicity.
Objectives in terms of knowledge :
Practical learning of in silico preparation of chemical libraries for virtual screening, based on the structure of reference ligands including a part i) generation of three-dimensional molecular models for small molecules (1D/2D to 3D), how to go from 1D-2D-3D ii) calculation of ligand descriptors, iii) pharmacokinetic aspects (ADME/tox) based on specific physicochemical criteria, iv) application of a ligand-based screening.
Targeted skills :
Students will discover, through specific examples, the main strategies to optimize an initial touch to the drug candidate and the marketed therapeutic molecule.
Several experimental approaches and rational in silico design methods can be used to transform a "hit" into a "lead" (X-ray diffraction, NMR, medicinal chemistry, SAR, QSAR, rescoring, molecular simulation, ligand-based, fragment-based methods...).
Several examples of optimization will be discussed with applications in infectious diseases, cancer, cardiovascular diseases and the reproductive system.
The aim of screening is to identify molecules with biological activity of therapeutic interest with respect to a therapeutic target. High throughput, in silico or in vitro, allows the testing of several thousand molecules per week. Pharmacological screening is the first step in the drug discovery process. The molecules identified during the initial screening phase (hits) are far from being drugs yet. Their binding to their target is still too weak, so they will have to be optimized (leads). Thanks to subtle and progressive transformations of the structure of the hit, the medicinal chemist and the drug designer will allow it to bind more efficiently to its target. However, this increase in affinity alone will not be enough to make the key a drug candidate. Before being evaluated in animal efficacy models and then in humans, the product will have to satisfy several other constraints: a) specificity, b) adequate bioavailability, c) appropriate pharmacokinetic properties, d) absence of toxicity.
Objectives in terms of knowledge :
Practical learning of in silico preparation of chemical libraries for virtual screening, based on the structure of reference ligands including a part i) generation of three-dimensional molecular models for small molecules (1D/2D to 3D), how to go from 1D-2D-3D ii) calculation of ligand descriptors, iii) pharmacokinetic aspects (ADME/tox) based on specific physicochemical criteria, iv) application of a ligand-based screening.
Targeted skills :
Students will discover, through specific examples, the main strategies to optimize an initial touch to the drug candidate and the marketed therapeutic molecule.