Fragment-based lead discovery

Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in molecular weight. It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity. FBLD can be compared with high-throughput screening (HTS). In HTS, libraries with up to millions of compounds, with molecular weights of around 500 Da, are screened, and nanomolar binding affinities are sought. In contrast, in the early phase of FBLD, libraries with a few thousand compounds with molecular weights of around 200 Da may be screened, and millimolar affinities can be considered useful. FBLD is a technique being used in research for discovering novel potent inhibitors. This methodology could help to design multitarget drugs for multiple diseases. The multitarget inhibitor approach is based on designing an inhibitor for the multiple targets. This type of drug design opens up new polypharmacological avenues for discovering innovative and effective therapies. Neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s, among others, also show rather complex etiopathologies. Multitarget inhibitors are more appropriate for addressing the complexity of AD and may provide new drugs for controlling the multifactorial nature of AD, stopping its progression. In analogy to the rule of five, it has been proposed that ideal fragments should follow the 'rule of three' (molecular weight < 300, ClogP < 3, the number of hydrogen bond donors and acceptors each should be < 3 and the number of rotatable bonds should be < 3). Since the fragments have relatively low affinity for their targets, they must have high water solubility so that they can be screened at higher concentrations. In fragment-based drug discovery, the low binding affinities of the fragments pose significant challenges for screening.

À propos de ce résultat

Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Publications associées (1)

Concepts associés (4)

Cours associés (17)

Séances de cours associées (43)

BIOENG-518: Methods: from disease models to therapy

This course will describe methods underlying translational approaches from disease modeling and characterization to therapeutic applications. The presented techniques will be complemented by hands-on

CH-640: Modern Organic chemistry-Highlights in the field

Total synthesis, Natural product, Green chemistry, nantioselective synthesis, Organo-catalysis, Lewis acid,Transition-metal, Drug discovery.

CH-641: Modern Organic chemistry-Trends in the field

Total synthesis, Natural product, Green chemistry,Enantioselective synthesis, Organo-catalysis, Lewis acid,Transition-metal, Drug discovery.

Fragment-based lead discovery

Lipinski's rule of five

Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would likely make it an orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most orally administered drugs are relatively small and moderately lipophilic molecules.

Hit to lead

Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO).

Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases

Stewart Cole, Benoit Lechartier, Yujie Li, Wei Zhu, Kai Li

We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.

Amer Chemical Soc2014

Découverte de médicaments à base de fractionnement : concepts et technologies CH-332: Medicinal chemistry

Couvre les concepts et les technologies de la découverte de médicaments à base de fragments, en explorant l'identification des impacts, l'optimisation du plomb et les méthodes de dépistage.

Découverte de médicaments à base de fractionnement : concepts et technologies

Couvre les concepts et les technologies de la découverte de médicaments à base de fragments, des méthodes d'identification des personnes touchées et de son application dans la découverte de médicaments à base de cibles.

Space 4 Healthcare: Les applications de la microgravité en biotechnologie MOOC: New Space Economy

Se penche sur les applications de la microgravité dans le domaine de la biotechnologie, en s'attaquant aux défis qui se posent sur Terre et aux solutions potentielles offertes par la production spatiale.