| 1. |
- Andersson, H.O., et al.
(författare)
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Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
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| 2. |
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| 3. |
- Asp, Håkan, et al.
(författare)
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Reflection-in-Action: a Trigger for Acquisition of Higher Horticultural Education Knowledge
- 2009
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Ingår i: Acta Horticulturae. - 0567-7572 .- 2406-6168. ; 832, s. 43-47
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Konferensbidrag (refereegranskat)abstract
- This paper addresses experiences from two examples where practical case studies were used as course starter in order to increase the operational knowledge but also as a tool for increased learning outcomes for theoretical knowledge. The first case presented was performed by freshmen enrolled into a two-year-long horticultural management program and involved greenhouse pot plant production. Each student working group was responsible for one production factor e. g., light, water or nutrients, on one out of four crops (chrysanthemum, poinsettia, basil and tomatoes). Within given frames the details of the study were formed by the students. During the course the trials were discussed in terms of production physiology, statistics, and presentation of results. The second case study discussed was performed by students at an advanced level of the M.Sc. program in Horticulture (5 years). The assignment was to build, and run, an automatic closed hydroponic growing system. The case study was given during the first week of the course with minimal instructions. The set-up was then used in the course for experiments on nutrient analysis, pH regulation, and plant biometrics. Results showed that both case studies had a positive effect on the learning outcome for both theoretical as well as operational knowledge. The cultivation system resulting from the case became a rich source for discussions within the student group and with the supervisors on various subjects during the course. The supervisors found a way, through the case studies, to meet students with different backgrounds on their individual knowledge level. It was also encouraging for the teachers to observe how the personal initiative from the students grew when working with the case studies. Details about the case studies and our experiences as a pedagogical tool are presented and discussed.
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| 4. |
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| 5. |
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| 6. |
- Gising, Johan, 1981-, et al.
(författare)
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Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
- 2014
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:5, s. 1790-1801
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Tidskriftsartikel (refereegranskat)abstract
- Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
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| 7. |
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| 8. |
- Hultén, Johan, et al.
(författare)
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Cyclic HIV-1 protease inhibitors derived from mannitol : synthesis, inhibitory potencies, and computational predictions of binding affinities
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 885-897
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Tidskriftsartikel (refereegranskat)abstract
- Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (la and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
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| 9. |
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| 10. |
- Hämäläinen, Markku D., et al.
(författare)
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Characterization of a set of HIV-1 protease inhibitors using binding kinetics data from a biosensor-based screen
- 2000
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 5:5, s. 353-359
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Tidskriftsartikel (refereegranskat)abstract
- The interaction between 290 structurally diverse human immunodeficiency virus type 1 (HIV-1) protease inhibitors and the immobilized enzyme was analyzed with an optical biosensor, Although only a single concentration of inhibitor was used, information about the kinetics of the interaction could be obtained by extracting binding signals at discrete time points. The statistical correlation between the biosensor binding data, inhibition of enzyme activity (K-i), and viral replication (EC50) revealed that the association and dissociation rates for the interaction could be resolved and that they were characteristic for the compounds. The most potent inhibitors, with respect to K-i and EC50 values, including the clinically used drugs, all exhibited fast association and slow dissociation rates. Selective or partially selective binders for HIV-1 protease could be distinguished from compounds that showed a general protein-binding tendency by using three reference target proteins. This biosensor-based direct binding assay revealed a capacity to efficiently provide high-resolution information on the interaction kinetics and specificity of the interaction of a set of compounds with several targets simultaneously.
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| 11. |
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| 12. |
- Karlen, Helena
(författare)
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Introduktion av nya grödor : svensk sötpotatis
- 2018
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Ingår i: LTV-fakultetens faktablad.
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Annan publikation (populärvet., debatt m.m.)abstract
- Efterfrågan på sötpotatis ökar stadigt och det finns goda förutsättningar att kunna odla denna i Sverige på friland. Sötpotatis, Ipomea batatas, tillhör familjen Convolvulaceae, inte potatisfamiljen och det vi kallar sötpotatis är lagringsrötter. Den förökas vegetativt, vanligtvis med sticklingar, och plantering och skörd tillhör utmaningarna.
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| 13. |
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| 14. |
- Karlen, Helena
(författare)
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Övervintring av plantskoleväxter hos plantskoleföretagarna : ett prioriterat förbättringsområde
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Alla plantskoleproducenter av fleråriga kulturer har ett behov av att skydda sina växter, oavsett om övervintringen sker på friland - med eller utan täckning eller om de tar in växterna i kyl. En risk finns alltid att växterna utvintrar eller vinterskadas så pass mycket att de inte kan säljas efterföljande säsong. Särskilt krukodlade är utsatta eftersom deras rotsystem befinner sig ovanför marken och blir därför mer utsatta för nederbörd och svängningar i lufttemperatur. Därför är det viktigt att fundera över hur växter bäst ska skyddas mot ogynnsam väderlek och att hitta metoder för att utvärdering av olika tillvägagångssätt. Mikroklimatet nära plantorna vid vintertäckning mäts sällan och det är därför mycket svårt att uttala sig om vilket sätt som skyddar plantorna bäst. För att kunna öka kunskapen om vilket vinterskydd som är bäst, testades en enkel utvärderingsmetod för krukodlade plantskoleväxter som fungerar oavsett placering i Sverige, och en mätning som går att göra oavsett om vintern är hård eller mild. Med hjälp av metoden kan kunskapsluckor identifieras och jämförelser göras mellan år och olika geografiska platser. Metodutvecklingsförsöket visade att metoden med loggar fungerar väl och ger tillförlitlig data genom hela vintertäckningen. I ett efterföljande steg vore det önskvärt att utarbeta en enkel metod för att kunna bedömning övervintrade plantors kondition och vitalitet.
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| 15. |
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| 16. |
- Lampa, Anna, et al.
(författare)
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Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:14, s. 5413-5424
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Tidskriftsartikel (refereegranskat)abstract
- Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
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| 17. |
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| 18. |
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| 19. |
- Lampa, Anna, et al.
(författare)
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Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
- 2014
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 5:3, s. 249-254
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Tidskriftsartikel (refereegranskat)abstract
- Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.
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| 20. |
- Lampa, Anna, et al.
(författare)
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P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 19:16, s. 4917-4927
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Tidskriftsartikel (refereegranskat)abstract
- Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the D-phenylglycine epimers.
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| 21. |
- Lampa, Anna, et al.
(författare)
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Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
- 2014
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 22:23, s. 6595-6615
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Tidskriftsartikel (refereegranskat)abstract
- With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
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| 22. |
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| 23. |
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| 24. |
- Nurbo, Johanna, et al.
(författare)
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β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:10, s. 5590-5605
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Tidskriftsartikel (refereegranskat)abstract
- In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-amino acid substitution, the P(1), P(2), and P(3) positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the alpha-peptide analogues. However, several compounds exhibited muM potency. Inhibition data were compared with modeled ligand-protein binding poses to understand how changes in ligand structure affected inhibition potency. The P(3) position seemed to be the least sensitive position for beta-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q(2)=0.48 and r(pred)(2)=0.68.
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| 25. |
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| 26. |
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| 27. |
- Rönn, Robert, et al.
(författare)
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Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:6, s. 2955-2967
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P-1 moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
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| 28. |
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| 29. |
- Wingren, Carola, et al.
(författare)
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Urbana nyanser av grönt : om grönskans roll i en förtätad klimatsmart stad
- 2015
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- I ett gränsöverskridande samarbete mellan universitet, kommun, stat och företag har vi i denna skrift försökt fånga och utveckla idéer om den urbana grönskans roll i en förtätad stad. Frågan är högaktuell när flertalet kommuner förtätar, för att minska transporter och koldioxidutsläpp samt bevaka intresset för den goda jordbruksmarken så att den fortsatt kan vara tillgänglig för livsmedelsförsörjning. Men förtätningen är inte bara av godo, om nära rekreationsområden försvinner och negativa extrema klimatsituationer som värmeöar, vindeffekter eller översvämningar uppstår. Därför vill vi se vårt arbete som ett inlägg i debatten om vart vi är på väg, med hantering av det offentliga rummet men också av det privata. I vårt arbete vill vi synliggöra de möjligheter som en grönare stadsplanering skulle kunna leda till, där tätt inte alltid är tätt, och där grönt nyanseras, såväl vad det gäller estetik, upplevelse, som biologisk mångfald, skötsel eller användning. Vi vill visa på att grönska i nya former kan bidra till att utveckla stadens mellanrum, och vi vill berätta om dess fördelar för att minska negativa effekter av en bebyggelseförtätning. Vi bidrar också med synpunkter på vilka frågor som bör ställas inför en förtätning i staden; om klimat, trygghet, mötesplatser, biologisk mångfald, men också om 'grön stadsbyggnadskonst' där en urban grön typologi och nya grönurbana begrepp och visioner behöver utvecklas. Vi som medverkat i projektet hoppas att denna skrift och tillhörande film, ska inspirera till vidare diskussion om vad tätt och grönt kan vara i en stad som utvecklas med hållbara förtecken.
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| 30. |
- Zuccarello, Guido, et al.
(författare)
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HIV-1 protease inhibitors based on acyclic carbohydrates
- 1998
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 63:15, s. 4898-4906
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Tidskriftsartikel (refereegranskat)abstract
- A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.
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| 31. |
- Örtqvist, Pernilla, et al.
(författare)
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Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:17, s. 6512-6525
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Tidskriftsartikel (refereegranskat)abstract
- Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.
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| 32. |
- Örtqvist, Pernilla, et al.
(författare)
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Phenylglycine as a Novel P2 Scaffold in Hepatitis C Virus NS3 Protease Inhibitors
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:3, s. 1448-1474
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Tidskriftsartikel (refereegranskat)abstract
- Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1–P3 cyclization, which gave products with inhibition constants in the nanomolar range (75 nM).
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| 33. |
- Örtqvist, Pernilla, et al.
(författare)
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Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V
- 2010
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Ingår i: Antiviral Therapy. - 1359-6535 .- 2040-2058. ; 15:6, s. 841-852
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors. METHODS: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results. RESULTS: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position. CONCLUSIONS: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme.
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