Design of Adenosine Kinase Inhibitors from the NMR-Based Screening of Fragments

Abstract

A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…3) and 59-amino-59-deoxyadenosine as lead compounds (Cottam et al, 1993;Kowaluk et al, 1998;Wiesner et al, 1999), which were studied kinetically for inhibition of purified ADK activity (Cottam et al, 1993). A valuable strategy to modify and optimize existing lead molecules to improve their potency, bioavailability, or toxicity profile is based on fragmentation of existing leads and NMR-based screening of those fragments with the goal to identify suitable replacement of the fragments and incorporation of the newly identified fragments into the original scaffold (Hajduk et al, 2000). Structure-activity relationships and computational studies led to the identification of a wide range of ADK inhibitors (Cowart et al, 2001;Zheng et al, 2001;Gfesser et al, 2003;Perner et al, 2003;Ugarkar et al, 2003;.…”

Protein NMR in biomedical research

“…Reverse screening An alternative method of lead optimization is fragmentation of the lead compound into component molecules, and screening for alternative fragments which are then incorporated back into the original lead [130]. This strategy is useful if a single fragment of a lead is suspected to add little or negative contributions to binding affinity, or to be responsible for poor physicochemical, pharmacokinetic or toxicological properties.…”

SAR by NMR: An Analysis of Potency Gains Realized Through Fragment‐linking and Fragment‐elaboration Strategies for Lead Generation

“…Values for pK D were derived as described in the text. Examples are given for adenosine kinase [28], PTP-1B [29,30], LFA [25], stromelysin [17,19], HCV protease [31], and FKBP [14].…”