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Quantitative structure-activity relationships of carbonic anhydrase inhibitors

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Progress in Drug Research

Part of the book series: Progress in Drug Research ((PDR,volume 60))

Summary

A review is presented of quantitative structure-activity relationships (QSARs) of different categories of carbonic anhydrase (CA) inhibitors, which are basically benzenesulfonamides, heterocyclic sulfonamides and aliphatic sulfonamides. The review shows that in all categories, the inhibition potency depends largely on the electronic properties of the sulfonamide group, which can be affected by the electronic characteristics of the substituents present on the nucleus (benzene or heterocyclic ring) of the sulfonamide molecules. Substituents themselves can be involved, along with the nucleus, in some dispersion interaction with the enzyme. Based on this review, a schematic model is presented to represent the interaction of sulfonamides with the CA.

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Abbreviations

AM1:

Austin model 1 (quantum mechanical method)

CA:

carbonic anhydrase

QSAR:

quantitative structure-activity relationship

K1 :

enzyme inhibition constant

k:

rate constant

K:

binding constant

υd :

14N nuclear quadrupole resonance difference frequency

kHz:

kiloHertz

IC50 :

inhibitor concentration leading to 50% inhibition of the enzyme

RA:

relative activity

BE:

binding energy

Evdw :

van der Waals interaction energy

Q:

atomic charge

EH :

energy of highest occupied molecular orbital

EL :

energy of lowest unoccupied molecular orbital

μ:

dipole moment of the molecule

μx, μy and μz :

components of μ in x-, y- and z-directions, respectively

Пxx, Пyy and Пzz :

polarizabilities of molecule along the axes of lowest, medium and highest inertia, respectively

П:

Пxx, Пyy and Пzz

COSMO:

conductive shielding model

ΔHS :

difference between heats of formation of vacuum and COSMO

d1 :

local dipole index based on Mulliken charges

fE :

frontier electron density electrophilic

SN :

nucleophilic superdelocalizability index

SE :

electrophilic superdelocalizability index

Pxx, Pyy and Pzz :

same as Пxx, Пyy and Пzz, respectively

Axx, Ayy and Azz :

lengths of the molecule in x-, y- and z-directions, respectively

1χv :

Kier’s first-order valence molecular connectivity index

Px :

electrotopological state (E-State) index of an atom x

hCA I and hCA II:

human CA isozymes of types I and II

bCA IV:

bovine CA isozyme of type IV

B5 :

Sterimol width parameter describing tha maximum width of a substitute

Vw :

van der Waals volume

Vs :

molar volume

π:

hydrophobic constant

σ:

Hammett’ electronic constant

P:

octanol-water partition coefficient

ClogP:

calculated logP.

n:

number of data points

r:

corelation coefficient

q2 :

cross-validated r2 obtained by leave-one-out jackknife procedure

s:

standard deviation

Fx,y :

F-ratio between the variances of calculated and observed activities (x:number of independent variables; y=n−x−1)

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  1. Department of Chemistry, Birla Institute of Technology and Science, Pilani, 333031, India

    Satya P. Gupta

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    Ernst Jucker

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Gupta, S.P. (2003). Quantitative structure-activity relationships of carbonic anhydrase inhibitors. In: Jucker, E. (eds) Progress in Drug Research. Progress in Drug Research, vol 60. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8012-1_6

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