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1.  Neoceptor Concept Based on Molecular Complementarity in GPCRs: A Mutant Adenosine A3 Receptor with Selectively Enhanced Affinity for Amine-Modified Nucleosides 
Journal of medicinal chemistry  2001;44(24):4125-4136.
Adenosine A3 receptors are of interest in the treatment of cardiac ischemia, inflammation, and neurodegenerative diseases. In an effort to create a unique receptor mutant that would be activated by tailor-made synthetic ligands, we mutated the human A3 receptor at the site of a critical His residue in TM7, previously proposed to be involved in ligand recognition through interaction with the ribose moiety. The H272E mutant receptor displayed reduced affinity for most of the uncharged A3 receptor agonists and antagonists examined. For example, the nonselective agonist 1a was 19-fold less potent at the mutant receptor than at the wild-type receptor. The introduction of an amino group on the ribose moiety of adenosine resulted in either equipotency or enhanced binding affinity at the H272E mutant relative to wild-type A3 receptors, depending on the position of the amino group. 3′-Amino-3′-deoxyadenosine proved to be 7-fold more potent at the H272E mutant receptor than at the wild-type receptor, while the corresponding 2′- and 5′-amino analogues did not display significantly enhanced affinities. An 3′-amino-N6-iodobenzyl analogue showed only a small enhancement at the mutant (Ki = 320 nM) vs wild-type receptors. The 3′-amino group was intended for a direct electrostatic interaction with the negatively charged ribose-binding region of the mutant receptor, yet molecular modeling did not support this notion. This design approach is an example of engineering the structure of mutant receptors to recognize synthetic ligands for which they are selectively matched on the basis of molecular complementarity between the mutant receptor and the ligand. We have termed such engineered receptors “neoceptors”, since the ligand recognition profile of such mutant receptors need not correspond to the profile of the parent, native receptor.
PMCID: PMC3413945  PMID: 11708915
2.  Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design 
Journal of medicinal chemistry  2001;44(13):2080-2093.
In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH’s provided details of how the adenosyl moiety of NAD+ interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH’s. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N6-(1-naphthalenemethyl)-2′-deoxy-2′-(3-methoxybenzamido)adenosine (6e), N6-(substituted-naphthalenemethyl)-2′-deoxy-2′-(substituted-benzamido)adenosine analogues were investigated. N6-(1-Naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (6m), N6-[1-(3-hydroxy-naphthalene)methyl]-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (7m), N6-[1-(3-methoxy-naphthalene)methyl]-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (9m), N6-(2-naphthalene-methyl)-2′-deoxy-2′-(3-methoxybenzamido)adenosine (11e), and N6-(2-naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC50’s of these compounds were in the range 2–12 μM for T. brucei, T. cruzi, and L. mexicana GAPDH’s, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure–activity relationships of this class of compounds, a library of 240 N6-(substituted)-2′-deoxy-2′-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N6 and C2′ substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH’s in the low micromolar range. We also explored adenosine analogues containing 5′-amido substituents and found that 2′,5′-dideoxy-2′-(3,5-dimethoxy-benzamido)-5′-(diphenylacetamido)adenosine (49) displays an IC50 of 60–100 μM against the three parasite GAPDH’s.
PMCID: PMC2957370  PMID: 11405646

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