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The insulin regulated aminopeptidase (IRAP) has been proposed as an important therapeutic target for indications including Alzheimer’s disease and immune disorders. To date, a number of IRAP inhibitor designs have been investigated but the total number of molecules investigated remains quite small. As a member the M1 aminopeptidase family, IRAP shares numerous structural features with the other M1 aminopeptidases. The study of those enzymes and the development of inhibitors provide key learnings and new approaches and are potential sources of inspiration for future IRAP inhibitors.

The insulin regulated aminopeptidase (IRAP) has been proposed as an important therapeutic target for indications including Alzheimer's disease and immune disorders. To date, a number of IRAP inhibitor designs have been investigated but the total number of molecules investigated remains quite small. As a member the M1 aminopeptidase family, IRAP shares numerous structural features with the other M1 aminopeptidases. The study of those enzymes and the development of inhibitors provide key learnings and new approaches and are potential sources of inspiration for future IRAP inhibitors. [ABSTRACT FROM AUTHOR]

Rational approaches for the design of enzyme inhibitors furnish powerful strategies for developing pharmaceutical agents and tools for probing biological mechanisms. A new strategy for the development of gem -disubstituted substrate-product analogues as inhibitors of racemases and epimerases is elaborated using α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis ( Mt MCR) as a model enzyme. Mt MCR catalyzes the epimerization at C 2 of acyl-CoA substrates, a key step in the metabolism of branched-chain fatty acids. Moreover, the human enzyme is a potential target for the development of therapeutic agents directed against prostate cancer. We show that rationally designed, N , N -dialkylcarbamoyl-CoA substrate-product analogues inactivate Mt MCR. Binding greatly exceeds that of the substrate, ( S )-ibuprofenoyl-CoA, up to ∼250-fold and is proportional to the alkyl chain length (4–12 carbons) with the N , N -didecyl and N , N -didodecyl species having competitive inhibition constants with values of 1.9 ± 0.2 μM and 0.42 ± 0.04 μM, respectively. The presence of two decyl chains enhanced binding over a single decyl chain by ∼204-fold. Overall, the results reveal that gem -disubstituted substrate-product analogues can yield extremely potent inhibitors of an epimerase with a capacious active site. [ABSTRACT FROM AUTHOR]

Abstract: Fragment-based virtual library design and virtual screening have been conducted against malic enzyme (ME) homology model. Several scaffolds have been identified as promising motifs to target ME’s NADP binding site. One small focused library has been synthesized and tested against ME. Several compounds from this library have shown sub-micromolar inhibitory activity against malic enzyme. [Copyright &y& Elsevier]