Ligand-based drug design of novel aldose reductase inhibitors.

Abstract

Future Medicinal ChemistryVol. 10, No. 21 EditorialFree AccessLigand-based drug design of novel aldose reductase inhibitorsMagdaléna MájekováMagdaléna Májeková*Author for correspondence: Tel.: +421 232 295 709; Fax: +421 254 775 928; E-mail Address: magdalena.majekova@savba.sk Department of Biochemical Pharmacology, Center of Experimental Medicine SAS, Institute of Experimental Pharmacology & Toxicology, Slovak Academy of Sciences, Bratislava, SlovakiaSearch for more papers by this authorPublished Online:30 Nov 2018https://doi.org/10.4155/fmc-2018-0127AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: aldose reductase inhibitorsdiabetes mellitus Type 2electrostaticsligand-based drug designCurrent state of design of aldose reductase inhibitorsProportionally to the increasing number of patients with diabetes mellitus, the late diabetic complications cause serious health problems worldwide. Aldose reductase (AR) is as a rate-limiting enzyme in the polyol pathway, one of the main mechanisms of glucose toxicity. Attempts to find efficient and safe inhibitors of aldose reductase (ARIs) are dated early after the very identification of AR [1]. However, from the group of AR inhibitors, there is only one compound used clinically (epalrestat). A further candidate, fidarestat, is expected to appear among US FDA approved drugs in the near future.Compounds found and proven in preclinical research as prospective drugs failed in clinical trials either for excessive adverse effects or due to a weak bioavailability. For this reason, the strategies in search of new ARIs should be reconsidered in order to identify the strong and poor sides of each drug design methodology in this field. This editorial is to point out the specific potential characteristic for ligand-based drug design of ARIs.Specific features of ARAldose reductase (EC: 1.1.1.21) belongs to the aldo-keto reductase superfamily [2]. The enzyme is important for many metabolic processes, but its main role in the framework of the polyol pathway is to catalyze the NADPH-dependent conversion of glucose to sorbitol with simultaneous change of NADPH to NADP+. Under pathologic conditions, this leads to accumulation of sorbitol in cells and destruction of tissues. The 3D structure of AR has been explored in many research works. Besides, numerous x-ray crystallographic works, also a neutron diffraction experiment was documented [3]. The catalytic mechanism was discussed in detail by Blakeley et al. [4].AR catalyzes many substrates, as lipid aldehydes, methyl glyoxal, aliphatic and aromatic aldehydes, daunorubicin, doxorubicin among others. [5]. With the exception of PGH2 transformation to PGD2, which proceeds in the absence of cofactors NADPH or NADP+, all other known catalytic processes of AR are NADPH-dependent. Participation of the cofactor NADPH means that the whole catalysis is a two-substrate process (sequentially ordered bi–bi process), a fact not often discussed in the evaluation of AR inhibition experiments [6]. In the first step of the process of aldehyde reduction, for example, glucose to alcohol (e.g., sorbitol), the enzyme binds with NADPH (the first substrate), which induces the conformational changes to create a binary complex E*•NADPH. Only this complex is able to bind aldehyde (the second substrate), which also provokes the formation of a new (yet ternary) complex E*•NADPH•aldehyde, readily changed via multistep reaction [4] and consumption of one proton to E*•NADP+•alcohol complex (i.e., complex of the enzyme with both products). Leaving the second substrate, the enzyme is in the state E*•NADP+, which is known as an object for binding of most AR inhibitors. Without binding of an inhibitor, NADP+ is released and the enzyme relaxes to the initial state.In the framework of this process, there are only two steps when inhibition could be achieved by an external compound: Before NADPH binding and subsequent fixation of the ‘safety-belt’, in other words, pushing the loop of residues Gly213–Leu226 to [7];After leaving the second product, in other words, by attacking the complex E*•NADP+.Structurally, almost all inhibitors known so far were identified in complex with E*•NADP+ [8,9]. The glutathione analog S-(1,2-dicarboxyethyl) glutathione (DCEG) was found to be a competitive inhibitor of AR with glutathione-propanal as substrate [10]. The complex of AR with DCEG and NADPH provided the only ternary structure of the complex of AR, cofactor and inhibitor with NADPH and not NADP+ (pdb 2f2k, [11]). In contrast to the product-like ligands, as lidorestat or fidarestat, DCEG represents substrate-like inhibitors.Further determining property of AR, which is important for ligand-based drug design, is a dependence of AR catalytic activity on pH. The optimum value of pH for the catalysis of aldehydes as glucose or glyceraldehyde is 6.2; however, the reduction of PGH2 to PGD2 (in the absence of NADPH) requires the optimum value of pH = 8.5, while the same substrate is reduced to PGF2 in the presence of NADPH optimally at pH = 5.0 [12]. Acidic conditions induce protonation of two important parts of the active site of the enzymatic complex: His110 (which often interacts with inhibitors via H-bond) and NADP+. As the resulting effect, the cavity of the active site is becoming more positive, when compared with the surrounding protein surface and physiological pH.Electrostatics of the active site works as a driving force for attracting the negatively charged acetic groups of such inhibitors as zopolrestat, epalrestat or lidorestat, which are inhibitors derived from the first known compounds capable to inhibit AR – organic acids [1]. Electrostatic interaction, mainly one of the first orders (charge–field interaction) belongs to the long-range interactions. As such, it is proper to drive a molecule from the larger distance, but alone it is not so good for stabilization of the molecule in the active site, as the energetic minimum of this interaction is broader than that of others (e.g., H-bond interaction). In the situation when inhibition means to prevent release of the co-factor from the protein, this interaction is not sufficient. Inhibitors with acetic functional group are therefore the best example of ligand-based design of ARIs. Coming from organic acids, researchers proposed structures which provided more and more interactions with residues of the active site. Besides, the hydrophobic interaction between methyl of acetyl group and nicotinamide ring, which is typical for all inhibitors of this type, we can observe an increasing number of H-bonds when inspecting inhibitors from weak to strong (alrestatin, epalrestat, tolrestat, zenarestat, cemtirestat, zopolrestat, lidorestat; corresponding pdb structures 1az1, 4jir, 2fzd, 1iei, 4qx4, 2fz8, 1z3n). The tricyclic framework, combining the skeleton rigidity with the proper placement of the functional acetyl group, was found to be advantageous for exact setting of new substituents which could ensure other properties, for example, high selectivity toward aldehyde reductase [13].Hydantoin derivativesSorbinil, the first representative of hydantoin AR inhibitors, was designed without exact knowledge of the ALR2 binding site, only as an attempt to mimic the substrate glucose or the co-factor NADPH. Although, the clinical trials did not confirm the in vivo activity expected, it was later often used for molecular modeling studies and gave rise, on the basis of ligand-based design, to the most prospective hydantoin inhibitor – fidarestat [14].Inhibitors of natural originNatural compounds have a long tradition in the treatment of diabetes, mainly in the traditional Chinese medical system, which has categorized diabetes as a separate disease [15]. Recent studies, re-established with means of modern experimental methods, found a large number of natural compounds able to affect chronic diabetic complications. Many of them are able to inhibit AR. The 4-hydroxycoumarin, 4,2′,4′-trihydroxychalcones, tetra- and penta-O-galloyl-glucosides, as well as ellagic acid and its derivatives proved to be the most efficient inhibitors with IC50 achieving the value 0.02 μm/l [16]. On taking polyphenolic compounds as leads for ligand-based design of ARIs, a harder control is required due to the greater risk for pan-assay interference compounds (PAINS) character.Future perspectiveIn order to find an efficient and safe drug from the group of ARIs means, besides constructing a powerful inhibitor, to avoid the reasons of clinical trial failures, in other words, adverse effects and a low bioavailability. To fulfill the first condition, a high selectivity toward aldehyde reductase should be achieved, which is connected with interaction of a ligand and residues of the so-called specificity pocket, mainly with Leu300, Phe122 and Trp219. Creating an H-bond with Leu300 seems to be the best guarantee of high selectivity, as was observed also for fidarestat [17]. Opening the specificity pocket is often, yet not always, connected with selectivity [18].Carboxylic acid derivatives wearing a negatively charged group are often handicapped for their low bioavailability. However, the real transport through membrane compartments is given by the total permeability coefficient, not only by partitioning, as in each hydrophilic compartment the almost same acid-basic balance is established. Indole compounds, even when wearing an acetyl substituent, have reasonable values of the permeability coefficient [19].The last point to be emphasized is the necessity of joining the ARI activity with another type of molecular mechanism, creating thus the compound with polypharmacological effect. Diabetes is a multifactorial disease and therefore needs a multi-target approach in designing new drugs. For this aim, the ligand-based approach is a good choice.Financial and competing interests disclosureThis work was supported by the grants of the Slovak Research and Development Agency under the contract No. APVV-15-0455 and the Scientific Grant Agency VEGA grant 2/0127/18. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Hayman S, Kinoshita JH. Isolation and properties of lens aldose reductase. J. Biol. Chem. 240, 877–882 (1965).Crossref, Medline, CAS, Google Scholar2 Mindnich RD, Penning TM. Aldo-keto reductase (AKR) superfamily: genomics and annotation. Hum. Genomics 3, 362–370 (2009).Crossref, Medline, CAS, Google Scholar3 Hazemann I, Dauvergne MT, Blakeley MP et al. High-resolution neutron protein crystallography with radically small crystal volumes: application of perdeuteration to human aldose reductase. Acta Crystallogr. D Biol. Crystallogr. 61(Pt 10), 1413–1417 (2005).Crossref, Medline, CAS, Google Scholar4 Blakeley MP, Ruiz F, Cachau R et al. Quantum model of catalysis based on a mobile proton revealed by subatomic x-ray and neutron diffraction studies of h-aldose reductase. PNAS 105, 1844–1848 (2008).Crossref, Medline, CAS, Google Scholar5 Oppermann U. Complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology. Annu. Rev. Pharmacol. Toxicol. 47, 293–322 (2007).Crossref, Medline, CAS, Google Scholar6 Petrash JM. All in the family: aldose reductase and closely related aldo-keto reductases. Cell. Mol. Life Sci. 61, 737–749 (2004).Crossref, Medline, CAS, Google Scholar7 Biadene M, Hazemann I, Cousido A et al. The atomic resolution structure of human aldose reductase reveals that rearrangement of a bound ligand allows the opening of the safety-belt loop. Acta Crystallogr. D Biol. Crystallogr. 63(Pt 6), 665–672 (2007).Crossref, Medline, CAS, Google Scholar8 Klebe G, Krämer O, Sotriffer C. Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations. Cell. Mol. Life Sci. 61, 783–793 (2004).Crossref, Medline, CAS, Google Scholar9 Maccari R, Ottanà R. Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions. J. Med. Chem. 58, 2047–2067 (2015).Crossref, Medline, CAS, Google Scholar10 Dixit BL, Balendiran GK, Watowich SJ et al. Kinetic and structural characterization of the glutathione-binding site of aldose reductase. J. Biol. Chem. 275, 21587–21595 (2000).Crossref, Medline, CAS, Google Scholar11 Singh R, White MA, Ramana KV et al. Structure of a glutathione conjugate bound to the active site of aldose reductase. Proteins 6, 101–110 (2006).Crossref, Google Scholar12 Nagata N, Kusakari Y, Fukunishi Y et al. Catalytic mechanism of the primary human prostaglandin F2a synthase, aldo-keto reductase 1B1 – prostaglandin D2 synthase activity in the absence of NADP(H). FEBS J. 278, 1288–1298 (2011).Crossref, Medline, CAS, Google Scholar13 Majekova M, Ballekova J, Prnova M et al. Structure optimization of tetrahydropyridoindole-based aldose reductase inhibitors improved their efficacy and selectivity. Bioorg. Med. Chem. 25, 6353–6360 (2017).Crossref, Medline, CAS, Google Scholar14 Oka M, Matsumoto Y, Sugiyama S et al. A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2′, 5′-dioxospiro[chroman-4,4′-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by x-ray crystallography. J. Med. Chem. 43, 2479–2483 (2000).Crossref, Medline, CAS, Google Scholar15 Li WL, Zheng HC, Bukuru J et al. Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. J. Ethnopharmacol. 92, 1–21 (2004).Crossref, Medline, CAS, Google Scholar16 Kawanishi K, Ueda H, Moriyasu M. Aldose reductase inhibitors from the nature. Curr. Med. Chem. 10, 1353–1374 (2003).Crossref, Medline, CAS, Google Scholar17 El-Kabbani O, Carbone V, Darmanin C et al. Structure of aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity. J. Med. Chem. 48, 5536–5542 (2005).Crossref, Medline, CAS, Google Scholar18 Stefek M, Soltesova Prnova M, Majekova M et al. Identification of novel aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold. J. Med. Chem. 58, 2649–2657 (2015).Crossref, Medline, CAS, Google Scholar19 Bean RC, Shepherd WC, Chan H. Permeability of lipid bilayer membranes to organic solutes. J. Gen. Phys. 52, 495–508 (1968).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByAdvances in computer-aided drug design for type 2 diabetes7 March 2022 | Expert Opinion on Drug Discovery, Vol. 17, No. 5Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications12 May 2021 | Molecules, Vol. 26, No. 10Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway6 July 2020 | Carcinogenesis, Vol. 41, No. 9Mechanistic inhibition of non-enzymatic glycation and aldose reductase activity by naringenin: Binding, enzyme kinetics and molecular docking analysisInternational Journal of Biological Macromolecules, Vol. 159Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity10 December 2019 | Journal of Medicinal Chemistry, Vol. 63, No. 1 Vol. 10, No. 21 Follow us on social media for the latest updates Metrics History Received 19 April 2018 Accepted 20 April 2018 Published online 30 November 2018 Published in print November 2018 Information© 2018 Newlands PressKeywordsaldose reductase inhibitorsdiabetes mellitus Type 2electrostaticsligand-based drug designFinancial and competing interests disclosureThis work was supported by the grants of the Slovak Research and Development Agency under the contract No. APVV-15-0455 and the Scientific Grant Agency VEGA grant 2/0127/18. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download