Structure−Activity Relationships for Inhibition of Inosine Monophosphate Dehydrogenase by Nuclear Variants of Mycophenolic Acid

Nelson, Peter H.; Carr, Stephen F.; Devens, Bruce H.; Eugui, Elsie M.; Franco, Fidencio; González, Caleb; Hawley, Ralph C.; Loughhead, David G.; Milan, David J.; Papp, Eva; Patterson, John W.; Rouhafza, Sussan; Sjogren, Eric B.; Smith, David B.; Stephenson, Rebecca A.; Talamás, Francisco X.; Waltos, Ann-Marie; Weikert, Robert J.; Wu, John C.

doi:10.1021/jm9603633

Cited by 48 publications

(15 citation statements)

References 45 publications

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“…A data set of 73 small molecule IMPDH inhibitors and their biological activities (IC 50 values) were taken from the literature (18,19). The test set of 15 molecules was chosen at random from the original data set, which was used to determine the external predictivity of the resulting 3D‐QSAR models.…”

Section: Methodsmentioning

confidence: 99%

Computational Insights into the Inhibition of Inosine 5′‐Monophosphate Dehydrogenase by Mycophenolic Acid Analogs: Three‐Dimensional Quantitative Structure–Activity Relationship and Molecular Docking Studies

Yang

Wang

et al. 2012

Chem Biol Drug Des

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Inosine 5¢-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis of guanosine nucleotides. It is considered as an important target in the quest for drugs in the immunosuppressive, antiviral, antibacterial, and anticancer therapeutic areas. Herein, we report the 3D-QSAR analyses using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and docking on mycophenolic acid derivates for the first time. We obtained cross-validated q 2 value of 0.805 for CoMFA and 0.620 for CoMSIA, while the noncross-validated r 2 values for them were 0.969 and 0.935, respectively. Based on the CoMFA and CoMSIA contour maps and docking analyses, some key structural factors responsible for inhibitory activity were revealed. The results obtained from this study could be used for the rational design of potent inhibitors against IMPDH. Inosine 5¢-monophosphate dehydrogenase (IMPDH, EC. 1.1.1.205), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide (NAD)-dependent oxidation of inosine 5¢-monophosphate (IMP) to xanthosine 5¢-monophosphate (XMP) (1-3), XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). Inosine 5¢-monophosphate also serves as a substrate for the two-step biosynthesis of adenosine 5¢-monophosphate (AMP). An adequate pool of purine nucleotides depending on IMPDH is essential for cell proliferation, cell signaling, and as an energy source (4). Inhibition of IMPDH both depletes guanine nucleotides and increases adenine nucleotide pools, which causes a variety of biological responses. Such misregulation of metabolic pathways may be more consequential than the simple lack of guanine nucleotides.Two isoforms of the enzyme have been identified and designated as type I and type II, which possess 84% sequence identity, encoded by two separate genes located on chromosomes 7 and 3, respectively. The genes both encode for proteins that have 514 amino acid residues (5,6). Studies in mice have shown deletion of IMPDH type II results in embryonic lethality (7). Additional mouse studies have shown that IMPDH type I is not essential for normal mouse development. It has also been shown that, in general, type I is constitutively expressed at low levels, while type II is markedly up-regulated in actively proliferating cell types, including cancer cells and activated peripheral blood lymphocytes (8-10). As a result, IMPDH type II has emerged as an attractive target in the quest for drug discovery in the immunosuppressive, antiviral, antibacterial, and anticancer therapeutic areas.There has been significant success in the discovery of IMPDH-targeted drugs thus far (11)(12)(13)(14)(15). The inhibitor such as mycophenolic acid (MPA), which was developed as an immunosuppressant to prevent kidney allograft rejection, is now finding potential use in treating cancer as well. The three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, such as comparative mole...

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Section: Methodsmentioning

confidence: 99%

Computational Insights into the Inhibition of Inosine 5′‐Monophosphate Dehydrogenase by Mycophenolic Acid Analogs: Three‐Dimensional Quantitative Structure–Activity Relationship and Molecular Docking Studies

Yang

Wang

et al. 2012

Chem Biol Drug Des

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“…As a result, new compounds are designed to evaluate their potential activity. It includes structural modifications of known IMPDH inhibitors and investigations of new substances, which were synthetically obtained or isolated from natural sources [30][31][32]35,36 .…”

Section: Impdh Inhibitors Used In Clinicmentioning

confidence: 99%

“…In literature we can find a lot of new analogs, unfortunately only a few of them exhibit interesting activity 3,35,36 . Moreover, immunosuppressive agents cause side effect like dose-limiting gastrointestinal (GI) toxicity upon MMF or MPA oral administration.…”

Section: New Potent Impdh Inhibitors Derived From Mpamentioning

confidence: 99%

Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

Cholewiński

Iwaszkiewicz-Grześ

Prejs

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inosine 50 -monophosphate dehydrogenase (IMPDH) is important molecular target for potential anticancer, antiviral, antibacterial and immunosuppressive agents. A lot of compounds were obtained to establish their activity toward this enzyme, and to improve therapeutic properties of IMPDH inhibitors used as the drugs. Some of the recently reported analogs exhibited promising results during in vitro and in vivo examinations in comparison to substances applied in clinic. In this review, we describe synthesis and biological activity evaluations of the newly designed IMPDH inhibitors.

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“…For instance, replacement of the phenolic hydroxyl group by an amino moiety leads to an increase of IC50 from 0:020 mM to 0:154 mM, an eight-fold reduction in potency (Figure 14.8). This phenolic hydroxyl group was identified to be essential for high potency in the inhibition of IMPDH (Nelson et al 1996). The structure indicates that this change from an OH-group to an NH 2 -group would cause the loss of one hydrogen bond in the network of MPA's OH-group with IMPDH's OH-of Thr333 and NH 2 -group of Gln441 (Figure 14.7B).…”

Section: Drug Design For the Cofactor Binding Site Of Inosine Monophomentioning

confidence: 99%

Structure‐Based Drug Discovery

Kan

Hambly

Debe

2004

Molecular Analysis and Genome Discovery

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Structure−Activity Relationships for Inhibition of Inosine Monophosphate Dehydrogenase by Nuclear Variants of Mycophenolic Acid

Cited by 48 publications

References 45 publications

Computational Insights into the Inhibition of Inosine 5′‐Monophosphate Dehydrogenase by Mycophenolic Acid Analogs: Three‐Dimensional Quantitative Structure–Activity Relationship and Molecular Docking Studies

Computational Insights into the Inhibition of Inosine 5′‐Monophosphate Dehydrogenase by Mycophenolic Acid Analogs: Three‐Dimensional Quantitative Structure–Activity Relationship and Molecular Docking Studies

Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

Structure‐Based Drug Discovery

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