Recent progress in fragment-based lead discovery

TY - JOUR

T1 - Recent progress in fragment-based lead discovery

AU - Schulz, Michele N.

AU - Hubbard, Roderick E.

PY - 2009/10

Y1 - 2009/10

N2 - Fragment-based methods have emerged as a new strategy for drug discovery. The main advantages are that useful starting points for lead identification for most targets can be identified from a relatively small (typically 1000-member) library of low molecular weight compounds. The main constraints are the need for a method that can reliably detect weak binding and strategies for evolving the fragments into larger lead compounds. The approach has been validated recently as series of compounds from various programs have entered clinical trials. Current new developments are focussing on application of the methods to targets where conventional HTS fails and to integration of fragments alongside HTS for more druggable targets. Here, we provide a brief summary of the key elements of fragment-based lead discovery (FBLD), review recent progress and provide a perspective on the challenges that remain for the field.

AB - Fragment-based methods have emerged as a new strategy for drug discovery. The main advantages are that useful starting points for lead identification for most targets can be identified from a relatively small (typically 1000-member) library of low molecular weight compounds. The main constraints are the need for a method that can reliably detect weak binding and strategies for evolving the fragments into larger lead compounds. The approach has been validated recently as series of compounds from various programs have entered clinical trials. Current new developments are focussing on application of the methods to targets where conventional HTS fails and to integration of fragments alongside HTS for more druggable targets. Here, we provide a brief summary of the key elements of fragment-based lead discovery (FBLD), review recent progress and provide a perspective on the challenges that remain for the field.

KW - X-RAY CRYSTALLOGRAPHY

KW - DRUG DISCOVERY

KW - KINASE INHIBITOR

KW - DESIGN

KW - NMR

KW - IDENTIFICATION

KW - POTENT

KW - CHEMISTRY

KW - LIBRARIES

KW - ENTHALPY

UR - http://www.scopus.com/inward/record.url?scp=70349425790&partnerID=8YFLogxK

U2 - 10.1016/j.coph.2009.04.009

DO - 10.1016/j.coph.2009.04.009

M3 - Article

SN - 1471-4892

VL - 9

SP - 615

EP - 621

JO - Current Opinion in Pharmacology

JF - Current Opinion in Pharmacology

IS - 5

ER -