QSARs on human carbonic anhydrase VA and VB inhibitors of some new not yet synthesized, substituted...

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Introduction

There are 16 α-carbonic anhydrase (CA, EC 4.2.1.1) iso-forms expressed in mammals, CA I–CA XV, two of which, CA VA and CA VB, being present in mitochondria1–5. These two isozymes are involved in several biosynthetic processes, such as ureagenesis, gluconeogenesis and lipogenesis1,2,6–8. As hCA VA/VB are involved in several biosynthetic processes catalysed by pyruvate carboxyl-ase, acetyl CoA carboxylase and carbamoyl phosphate synthetases I and II, providing the bicarbonate substrate to these carboxylating enzymes involved in fatty acid bio-synthesis, their inhibition may lead to the development of anti-obesity agents possessing a new mechanism of action8. Inhibition data for classical sulphonamide CA inhibitors (CAIs) used clinically, such as AZA (acet-azolamide), TPM (topiramate), ZNS (zonisamide) were obtained, together with inhibition data for aromatic/het-erocyclic sulphonamides possessing varied structures, incorporating phenacetyl, pyridylacetyl and thienylacetyl

tails act as potent inhibitors of human mitochondrial iso-forms VA and VB. Such compounds may be useful for the development of novel anti-obesity therapies9.

The prediction set includes molecules having unknown observed values of dependent property. The quantitative structure–activity relationships (QSAR) studies can be made in absence or in presence of certain prediction set. In the absence of the prediction set, the purpose of QSAR studies is the identification of the molecular features with the highest impact (favourable or unfavourable) on the biochemical activity. In the presence of the prediction set, the purpose is to identify the prediction set molecules having the largest computed activity.

The search for new human mitochondrial isoforms V (VA and VB) inhibitors is important for medicinal chemistry. Therefore, the structures of the prediction set molecules were selected mainly by their possibility to be synthesized in laboratory conditions and taking into account the commercial availability of the raw materials.

ReseaRch aRtIcle

QSARs on human carbonic anhydrase VA and VB inhibitors of some new not yet synthesized, substituted aromatic/heterocyclic sulphonamides as anti-obesity agent

Shalini Singh1 and Claudiu T. Supuran2

1QSAR & Cheminformatics Laboratory, Department of Chemistry, Bareilly College, Bareilly, India and 2Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Florence), Italy

abstractThis paper presents result of quantitative structure–activity relationships (QSAR) study realized with the PRECLAV, omega, brood and MOPAC software. The dependent property is the inhibitory activity against human carbonic anhydrase mitochondrial isoforms VA and VB. The calibration set includes 17 aromatic/heterocyclic sulphonamides incorporating phenacetyl, pyridylacetyl and thienylacetyl tails with three clinically used CA inhibitors namely AZA, TPM and ZNS molecules. The prediction set contains 24 others not yet synthesized substituted aromatic/heterocyclic sulphonamides having unknown observed values of activity. In the presence of prediction set, the predictive quality of QSAR of hCA VA (r2 = 0.9789, F = 418.115, r2

CV = 0.9689) and hCA VB (r2 = 0.9768; F = 379.717; r2CV = 0.9637) is large. The

obtained models suggest a slightly different inhibition mechanism for the two isoforms. Large percentage, in weight, of CONH molecular fragments seems to be favourable to inhibitory activity of both VA and VB.

Keywords: QSAR, omega, brood, PRECLAV, carbonic anhydrase VA, VB

Address for Correspondence: Shalini Singh, QSAR & Cheminformatics Laboratory, Department of Chemistry, Bareilly College, Bareilly, India. Tel: +91 581 2522224. E-mail: [email protected]

(Received 03 July 2011; revised 15 July 2011; accepted 17 July 2011)

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(5): 666–672© 2012 Informa UK, Ltd.ISSN 1475-6366 print/ISSN 1475-6374 onlineDOI: 10.3109/14756366.2011.606544

Journal of Enzyme Inhibition and Medicinal Chemistry

2012

27

5

666

672

03 July 2011

15 July 2011

17 July 2011

1475-6366

1475-6374

© 2012 Informa UK, Ltd.

10.3109/14756366.2011.606544

GENZ

606544

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QSARs on human carbonic anhydrase inhibitors as anti-obesity agent 667


Table 1. Structural details of hCA VA and VB inhibitor and their observed and estimated inhibitory activities (−log KI).

Com. no.See structure above n Y X

1X

2Obs. VA Est. VA Obs. VB Est. VB

1 A 0 H – – −0.85733 −0.896 −0.8451 −0.9322 A 0 F – – −0.83885 −0.925 −0.89763 −0.8893 A 0 Cl – – −0.88649 −0.905 −0.9345 −0.8944 A 0 Br – – −0.87506 −0.86 −0.93952 −0.9285 A 1 H – – −0.95904 −0.93 −0.85733 −0.9586 A 2 H – – −1.0086 −0.961 −0.90309 −0.9317 B – – – −0.88081 −0.954 −0.86923 −1.1518 C 0 H CH CH −0.82607 −0.851 −0.89763 −0.8029 C 1 H CH CH −0.9345 −0.884 −0.91908 −0.88910 C 2 H CH CH −0.90849 −0.915 −0.91381 −0.85211 C 0 F CH CH −0.91908 −0.879 −0.90849 −0.78712 C 0 Cl CH CH −0.91381 −0.86 −0.90849 −0.80613 C 0 Br CH CH −0.85126 −0.829 −0.77085 −0.76514 C 0 H N CH −0.83251 −0.855 −0.83251 −0.88515 C 0 H CH N −0.86332 −0.855 −0.95424 −0.897

(Continued)

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668 S. Singh and C. T. Supuran


Com. no.See structure above n Y X

1X

2Obs. VA Est. VA Obs. VB Est. VB

16 C 2 H CH N −0.88081 −0.918 −0.96848 −0.92217 D – – CH CH −0.92428 −0.936 −0.78533 −0.96418 AZA – – – – −1.79934 −1.823 −1.73239 −1.60919 ZNS – – – – −1.30103 −1.23 −3.78053 −3.76120 TPM – – – – −1.79934 −1.793 −1.47712 −1.5

The calibration set and the prediction setRecently one of our groups8 reported for the first inhibi-tion study against mitochondrial isoform hCA VA and VB with aromatic/heterocyclic sulphonamides incorporating phenyl(alkyl), halogenosubstituted-phenyl or 1,3,4-thiadi-azole-sulphonamide moieties and thienylacetamido; phen-acetamido and pyridinylacetamido tails. The aromatic/heterocyclic sulphonamides incorporating phenacetyl, pyridylacetyl and thienylacetyl tails with clinically used CA inhibitors such as AZA, TPM and ZNS (Table 1) were included in the calibration set. The inhibitory activity (as K

I

values, in the nanomolar to micromolar range for isozymes) was expressed by means of the equation A = −log K

I.

The prediction set contains 24 other not yet synthe-sized substituted aromatic/heterocyclic sulphonamides generated by Brood10 software (version 2.0.0, open eye science software, Santa Fe, USA), having unknown observed values of activity (Table 2). Brood uses the shape and attachment geometry of the query fragment to identify a family of similar fragments.

Methods and formulas

The minimum energy geometry, for each molecule in the calibration and prediction set, was obtained by the confor-mational search ability of the Omega v.2.4.311–13 (OpenEye Science Software, Santa Fe, USA) program. Isomeric SMILES notation was used as program input in order to avoid any influences on conformational model generation by pre-senting 3D seed structures. Omega employs a rule-based algorithm12,13 in combination with variants of the Merck molecular force field 94. For the generation of conformers, following parameters were used: a maximum of 200 con-formers per compound, an energy cut-off of 10 kcal/mol relative to global minimum identified from the search. The force field used was the 94s variant of the MMMF_NoEstat (Merck molecular force field11–13) that includes all MMFF terms except coulomb interactions. The RMSD fit value 2.0 Å was used to avoid redundant conformers.

The conformations of minimum energy obtained by molecular mechanics calculations were further minimized by quantum chemical calculations. The semi-empirical PM6 method14 included in the MOPAC 2009 software15 (Stewart Computational Chemistry, Colorado Springs, CO) optimized the geometry more rigorously. In MOPAC analysis, we used the following sequence of key-words: “PM6 Pulay gnorm = 0.01 shift = 50 geo-ok campk-ing mmok bonds vectors”.

In the next step, the MOPAC and PRECLAV software (Center of Organic Chemistry, Bucharest16,17) produced more than 500 “whole molecule” (global) descriptors including the value of some weighted functions and vir-tual fragmentation descriptors for each molecule. Set of descriptors includes parabolic functions of whole mol-ecule descriptors, calculated by PRECLAV. The statistical calculations used for obtaining the QSAR equations were done with PRECLAV as reported earlier17–25.

Using only the “significant” descriptors18 PRECLAV computes thousands of QSAR equations, i.e. multi-linear formulas of the dependent property.

A C C D0 k k= + .∑ (1)

Here “A” represents a dependent property (here the inhibitory activity defined above) and “k” is the number of descriptors in the set. Ordinary Least Square Method com-putes weighting factors C

k of predictors D

k. The PRECLAV

program does not compute errors related to regression coefficients. The “quality” of each QSAR was computed using usual statistical formulas that are a measure of agree-ment of observed/computed values of activity: standard error of estimation Se, Pearson square correlation r2, Fisher function F and cross-validated Pearson square correlation r2

CV . The concordance between the calculated/observed

values has been calculated using the quality function Q16,19 which possesses values in the interval {−1, 1}.

Q r k= CV2 . (N )/N, (2)

where r2CV

is cross-validated (Leave one out method) Pearson square linear correlation between computed/observed values and N is the number of molecules in the calibration set (here N = 20). By increasing the number of descriptors k, the quality Q of the equations increases, reaching a maximum, and then decreases. For predictions, the equation with the highest quality was used, the descrip-tors present in this equation being called “predictors”.

The relative Utility (U) of a certain predictor on depen-dent property values was computed by the Specific proce-dure16,20. The predictors which present a high value for U, within the range [0, 1000], may be considered very useful in estimating the activity, because they correlate very well with activity and do not correlate with other predictors. Each “useful” predictor offers ample information about the variation in activity from molecule to molecule.

After computing the Acalc

values of the inhibitory activ-ity for the prediction set molecules, PRECLAV arranged these molecules according to the estimated values. It

Table 1. (Continued).

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Table 2. The chemical structure of prediction set molecules not yet synthesized having unknown observed values of activity.

21 22 23

24 25 26

27 28 29

30 31 32

33 34 35

36 37 38

39 40 41

42 43 44

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computed the average value Acalc

m for the estimated val-ues and standard deviation σ of the estimated values. The program considers “high values” as the values fulfilling the criterion (3) and “low values” as the values fulfill-ing the criterion (4). Here, the molecules having “high” computed value of inhibitory activity have been taken as “recommended for synthesis21”.

A A 0.5 calc calcm> + σ. (3)

A A 0.5 calc calcm< − σ. (4)

PRECLAV divides the analyzed molecules into virtual fragments, using an algorithm reported earlier26,27. The virtual fragments identified by PRECLAV do not always coincide with the classical functional groups. The pres-ence of a significant fragment in the molecule greatly influences (in a positive of negative way) the inhibitory activity of the molecule.

Results and discussions

QSAR#1 (human mitochondrial isomers of hCA VA inhibitors)In absence of prediction set, the number of “significant” descriptors is 232 and we obtained type (1) QSAR equa-tion where

C0 = −1.6194;

C1 = 0.0163;

D1 is (psa) percentage of single conjugated and aro-

matic bonds16 (U = 1000);C

2 = −0.0164; and

D2 is (war) weight percentage of largest molecular

fragment16 (U = 994).Whereas the quality of correlation is described by the

statistical indices:Se = 0.0422, r2 = 0.9789, F = 418.1153, r2

CV = 0.9689,

Q = 0.8721.The quality of above QSAR is high. There are no outliers

in calibration set. The minimum correlation of predictors with inhibitory activity is computed for D

2 (r2 = 0.3535). The

inter-correlation between predictor is very low (r2 = 0.0296). Therefore, D

1 predictor offers a different kind of informa-

tion from the D2 predictor. In this study, molecules of ana-

lyzed database include 33 virtual fragments but only seven virtual flagments are considered significant. The percent-ages, in weight, of molecular fragments are well correlated (directly or inversely) with the values of inhibitory activity: CONH (r = 0.6851), C

2HN

3S

2 (r = −0.645), CH (r = −0.645),

C atom (r = −0.645), O atom (r = −0.645) and NH2 (r =

−0.5298).Because of the structure of the computed QSAR and the result of virtual fragmentation, we think:• the presence of substituted CONH groups (com-

pound no. 1–6 and 8–16) is favourable to activity;• the presence of C

2HN

3S

2 (compound no. 18), CH

(compound no.20), C atom (compound no. 20) and O atom (compound no. 20) fragments is unfavourable to the activity;

• the presence of aromatic and conjugated bonds is favourable to inhibitory activity; and

• the large molecular fragments are not significant to inhibitory activity. This conforms to the molecular fragment analysis of calibration set compounds.

Table 3. Calculated values of hCA VA and VB inhibitory activity for the molecules in the prediction set.S. no. Comp. no. (VA) Calculated VA Comp. no. (VB) Calculated VB21. 40. −0.704 25. −0.75222. 36. −0.725 26. −0.75723. 34. −0.727 30. −0.77724. 42. −0.728 37. −0.78325. 41. −0.73 32. −0.78426. 44. −0.776 31. −0.79527. 32. −0.779 35. −0.79728. 21. −0.785 34. −0.81229. 38. −0.803 36. −0.83530. 31. −0.808 40. −0.84531. 35. −0.811 33 −0.85532. 22. −0.819 39 −0.87333. 43. −0.841 38 −0.87634. 37. −0.842 22 −0.91435. 33. −0.842 27 −0.91836. 23. −0.867 23 −0.9337. 25. −0.867 41 −0.93138. 24. −0.88 24 −1.03739. 28. −0.89 44 −1.06640. 29. −0.893 21 −1.06941. 27. −0.9 28 −1.10542. 26. −0.9 29 −1.18143. 39. −0.919 43 −1.25544. 30. −0.922 42 −1.264

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In the presence of the prediction set, the number of “sig-nificant” descriptors is only 188. We obtained the same QSAR equation and results (r2 = 0.9789, F = 418.1153, r2

cv = 0.9689) in presence of the prediction set molecules

not yet synthesized substituted aromatic/heterocyclic sulphonamides. Therefore, the calibration set is quite “representative sample” in calibration set + prediction set group. Using this equation the maximum activity computed for calibration set molecules is −0.829, the average activity computed for calibration set molecules is −1.003 ± 0.288 and the average activity computed for prediction set molecules is −0.825 ± 0.067.

In Table 3, the calculated values identified by the pro-gram as “high” have been marked in bold letters, while the values identified as “low” have been underlined. According to criterion (3), this equation identified eight molecules in prediction set having “high values” of activity. The large number of molecules identified as “high active” in prediction set is, probably, the statistical effect of small gap between maximum and minimum observed value of activity in calibration set. However, in the Table 3 “most active” 75% molecules include chlorine atoms and CH

3

group and 25% include OH group. So the favourable effect of chlorine atoms and CH

3 group on activity is obvious.

QSAR# 2 (human mitochondrial isomers of hCA VB inhibitors)In absence of prediction set, the number of “significant” descriptors is 222 and we obtained type (1) QSAR equa-tion where

C0 = −4.3766;

C1 = 6.7015;

D1 is (XSC) maximum net charge of C atoms at para-

bolic region16 (U = 1000);C

2 = −10.0927; and

D2 is (avc) average free valence of C16 (U = 896).

Whereas the quality of correlation is described by the statistical indices:

Se = 0.102, r2 = 0.9768, F = 379.717, r2cv = 0.9637, Q = 0.8673.

The quality of above QSAR is also high. There are no outliers in calibration set. The minimum correlation of predictors with inhibitory activity is computed for D

2

(r2 = 0.056). The inter-correlation between descriptors is very low (r2 = 0.0303). In this study, molecules of analysed database include 33 virtual fragments but only three vir-tual fragments CONH (r = 0.5455), C

7H

4NO (r = −0.9396)

and NH2 (r = −0.788) are considered significant. Because

of the structure of the computed QSAR#2 and the result of virtual fragmentation, we think:• C

7H

4NO (compound no. 19) and NH

2 (compound

nos. 1–20) fragments are the unfavourable to the activity;

• the presence of substituted CONH (compound nos. 1–6 and 8–16) groups is favourable to activity;

• the avc is inversely proportional to the activity, if the free valance carbon is substituted by radical like Cl and OH increases the inhibitory activity; and

• the maximum net charge of C atoms is favourable to the inhibitory activity.

In the presence of the prediction set, the number of “sig-nificant” descriptors is only 184. We obtained the same QSAR equation and results (r2 = 0.9768 0; F = 379.717; r2

CV = 0.9637) in the presence of the prediction set molecules

not yet synthesized substituted aromatic/heterocyclic sul-phonamides. Therefore, in this case also the calibration set is quite “representative sample” in calibration set + prediction set group. Using the above QSAR equation, the maximum activity computed for calibration set molecules is −0.765, the average activity computed for calibration set molecules is −1.105 ± 0.662 and the average activity com-puted for prediction set molecules is −0.926 ± 0.154.

According to criterion (3), this equation identified 10 molecules in prediction set having “high values” of inhibitory activity for hCA VB. The Table 3 “most active” 70% molecules include halogen atoms and 30% molecule includes CH

3 and OH group. Favourable effect of halogen

atoms in activity is obvious in human mitochondrial iso-mers of hCA VB inhibitors.

conclusions

• Large percentage, in weight, of CONH molecular fragments seems to be favourable for the inhibitory activity of hCA VA and hCA VB.

• Large percentage, in weight, of CH3, C

2HN

3S

2, CH, C

atom, and O atom molecular fragments is unfavour-able to hCA VA inhibitory activity and C

7H

4NO and

NH2 molecular fragments are unfavourable to hCA

VB inhibitory activity.• Aromatic and single conjugated bond are favourable

for hCA VA inhibitory activity.• Maximum free valance of carbon atom is favourable

to the hCA VB inhibitory activity.• The positive correlation of maximum net charge of C

atoms plays dominating role of the modelling of hCA VB inhibitory activity.

• The “representative sample” feature of calibration set-in calibration set + prediction set group has a large influence on predictive power of computed QSAR. The most active ten molecules in VB and eight molecules in VA prediction set include halogen (chlorine atoms) group.

acknowledgement

The authors are thankful to OpenEye Scientific Software, Santa Fe, USA and Center of Organic Chemistry-Romanian Academy, Bucharest (Dr. Tarko L.) for provid-ing software for the QSAR study.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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QSARs on human carbonic anhydrase VA and VB inhibitors of some new not yet synthesized, substituted...

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