Molecular Features Related to HIV Integrase Inhibition Obtained from Structure- and Ligand-Based Approaches

<div><p>Among several biological targets to treat AIDS, HIV integrase is a promising enzyme that can be employed to develop new anti-HIV agents. The aim of this work is to propose a mechanistic interpretation of HIV-1 integrase inhibition and to rationalize the molecular features related to the binding affinity of studied ligands. A set of 79 HIV-1 integrase inhibitors and its relationship with biological activity are investigated employing 2D and 3D QSAR models, docking analysis and DFT studies. Analyses of docking poses and frontier molecular orbitals revealed important features on the main ligand-receptor interactions. 2D and 3D models presenting good internal consistency, predictive power and stability were obtained in all cases. Significant correlation coefficients (<i>r²</i> = 0.908 and <i>q²</i> = 0.643 for 2D model; <i>r²</i> = 0.904 and <i>q²</i> = 0.719 for 3D model) were obtained, indicating the potential of these models for untested compounds. The generated holograms and contribution maps revealed important molecular requirements to HIV-1 IN inhibition and several evidences for molecular modifications. The final models along with information resulting from molecular orbitals, 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selectivity within the chemical diversity of the data.</p></div

Influence of various fragment sizes for the model 6 with the combination A/B/C/H/Ch/DA.

<p>Influence of various fragment sizes for the model 6 with the combination A/B/C/H/Ch/DA.</p

Statistical parameters obtained from CoMFA analyses.

<p>Statistical parameters obtained from CoMFA analyses.</p

HOMO and LUMO for raltegravir (12) and for the most (2) and least active (37) molecules.

<p>HOMO and LUMO for raltegravir (12) and for the most (2) and least active (37) molecules.</p

HQSAR analyses using several fragment distinctions with standard fragment size (4–7 atoms).

<p><i>q²: cross-validated correlation coefficient; SEP: cross-validated standard error; r²: correlation coefficient; SEE: standard error of estimation; HL: hologram length; N: optimal number of components. Fragment distinction: A, atoms; B, bonds; C, connections; H, hydrogen atoms; Ch, chirality; DA, donor and acceptor.</i></p

3D contour maps for raltegravir (12), the most (2) and the least active ligand (37).

<p>Blue and red polyhedral indicate that substitution by positive and negative groups, respectively, can improve the biological activity. Green and yellow ones represent favorable and unfavorable steric regions, respectively.</p

Interactions between Mg²⁺ ions (left) and T66, K159 and K156 residues (right) and raltegravir drug (A and B), the most active (2) (C and D) and the least active (37) molecules from the data set (E and F).

<p>Interactions between Mg²⁺ ions (left) and T66, K159 and K156 residues (right) and raltegravir drug (A and B), the most active (2) (C and D) and the least active (37) molecules from the data set (E and F).</p

Application of bioisosterism in design of the semicarbazone derivatives as cruzain inhibitors: a theoretical and experimental study

<p>A series of semicarbazone, thiosemicarbazone, and aminoguanidine derivatives were synthesized and tested as antitrypanosomal agents. The theoretical NMR of the compounds was calculated using molecular modeling techniques (density functional theory (DFT) calculations) and confirmed the formation of the compounds. The ability to inhibit cruzain and <i>Trypanosoma cruzi</i> epimastigote replication was evaluated. Cruzain inhibition ranged between 70 and 75% (100 μM), and IC₅₀ values observed in epimastigote forms of <i>T. cruzi</i> ranged from 20 to 140 μM. Furthermore, the compounds did not present cytotoxicity at concentrations up to 50 and 250 μM in MTT tests. Molecular modeling studies were conducted using DFT method (B3LYP functional and the basis set 6-311G(d,p)) to understand the activity of the compounds, corroborating the observed cruzain inhibitory activity. In docking studies, the obtained analogs showed good complementarity with cruzain active site. In addition, docking results are in accordance with the susceptibility of these analogs to nucleophilic attack of the catalytic Cys25. Taken together, this study shows that this class of compounds can be used as a prototype in the identification of new antichagasic drugs.</p