On the inhibition of alcohol dehydrogenase: Shape group analysis of molecular electrostatic potential on van der Waals surfaces for some pyrazole derivatives

Abstract

The assessment of molecular similarity between molecules is a fundamental task in computer-aided drug design. In this work, we have applied a combined analysis of steric and electrostatic properties of a series of inhibitors of liver alcohol dehydrogenase ( LADH) to rationalize their action. The methodology is based on a topological characterization of the distribution of molecular electrostatic potential (MEP) on the fused-sphere van der Waals surface of a molecule. The topological description can be rendered in the form of two-dimensional diagrams that allow a quick visual or algorithmic analysis of the most relevant shape features of a molecule. By using the representations mentioned above (topological information as a function of the MEP), one can correlate this "structural" information with the values of inhibition constants K, for compounds with different levels of inhibitory activity. This approach allows one to have quantitative measures of similarity for related molecules and to eventually propose compounds that may exhibit a desired activity. The compounds analyzed in this work are a series of substituted derivatives of pyrazole, which span a relatively wide range of inhibitory powers. We have studied the role of the nature of the substituent, as well as its substitutional position, on the molecular shape and correlated these findings with the activity of each compound. Some consequences on the mechanism of inhibition of LADH are also discussed.

Heuristic molecular lipophilicity potential (HMLP): A 2D‐QSAR study to LADH of molecular family pyrazole and derivatives

“…It was found that the inhibitory power increases by a factor of 2 for each added methylene group CH 2 of the hydrocarbon substitutes in position 4. 32,36 In Table 1, the lipophilic indices, l s (8) , of hydrocarbon substitutes increase regularly with the number of carbon atoms by an increment of 0.033 per CH 2 , consistent with the experimental observation. In the next section, we focus on the QSAR relationship between molecular bioactivities and lipophilicity indices of pyrazole derivatives.…”

“…The interaction with the metallic cation seems to be essential for the release of the NOH proton to create the bond between pyrazole and NAD. 36,43 HMLP calculations of this research show that nonprotonated nitrogen N(2) is the most hydrophilic atom; therefore, it is easily bound with the zinc cation through electrostatic interaction. It was found that the inhibitory power increases by a factor of 2 for each added methylene group CH 2 of the hydrocarbon substitutes in position 4.…”

“…It has been proposed that the nonprotonated nitrogen N(2) binds to the zinc cation Zn(II) and the protonated N(1) forms a weak bond to the C(4) atom of the nicotinamide ring. 32,36 (cf. Fig.…”

“…The logarithms of experimental inhibition constants 36,40,48,49 logK I are correlated with HMLP indices through a linear regression equation, and the sensitive coefficients of HMLP indices are determined by PLS. 44 Experiments 36 show that the inhibitory power of a pyrazole derivative is enhanced by lipophilic substitutes on position 4. Both lipophilic and hydrophilic substitutes on position 3 lower the inhibitory power.…”

Computer Aided Drug Design: Some Fundamental Aspects

“…Here we shall provide only a brief summary of these results and some of the literature references involving applications of various relevant topological shape analysis methods [17,18,20,49,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66]. Shape analysis studies of some macromolecules, including proteins, were the very first to derive high accuracy, quantum chemistry quality electron densities for proteins and for drug molecules such a taxol [17,18,20,55], and for the construction of efficient lipophilicity potentials [49,62].…”