Molecular modeling studies of N-substituted pyrrole derivatives—Potential HIV-1 gp41 inhibitors

doi:10.1016/j.bmc.2007.12.034

Bioorganic & Medicinal Chemistry

Volume 16, Issue 6, 15 March 2008, Pages 3039-3048

https://doi.org/10.1016/j.bmc.2007.12.034 Get rights and content

Abstract

2D-, 3D-QSAR and docking studies were carried out on 23 pyrrole derivatives, to model their HIV-1 gp41 inhibitory activities. The 2D, 3D-QSAR studies were performed using CODESSA software package and comparative molecular field analysis (CoMFA) technique, respectively. The CODESSA five-descriptor model has a correlation coefficient R² = 0.825 and a standard deviation s² = 0.132. The 3D-QSAR CoMFA study allowed to obtain a model showing a good correlative and predictive capability which statistical results, provided by a eight-component regression equation, are: R² = 0.984, q² = 0.463, s = 0.119. Docking studies were employed to determine probable binding conformation of these analogues into the gp41 active site using the AutoDock program whose results were found complementary with thus of 2D- and 3D-QSAR analysis. These findings provide guidance for the design and structural modifications of these derivatives for better anti-HIV-1 activity which is important for the development of a new class of entry inhibitors.

Graphical abstract

Introduction

It is well known that the human immunodeficiency virus (HIV), the origin of the acquired immunodeficiency syndrome (AIDS) still remains a major cause of death.¹ The infection with HIV is characterized clinically by an inexorable decline in immune functions, leading to fatal consequences. The ability to inhibit viral replication is currently achieved in most patients with the so-called highly active antiretroviral therapy,² a combination of viral protease inhibitors³ and nucleosidic, non-nucleosidic or nucleotidic reverse transcriptase inhibitors.4, 5 This combination therapy has been remarkably successful in reducing viral load and has led to a decline in morbidity and mortality.6, 7 Unfortunately, most of these molecules present numerous shortcomings such as viral resistances⁸ and adverse effects.9, 10 In addition, these drugs are involved to later stages of infection.¹¹ Therefore, it is necessary to develop new drugs which are able to block the first steps of viral cycle life.

The fusion and entry of HIV into susceptible cells are mediated by its envelope glycoproteins gp41 and gp120.¹² Gp120 directs the virus to the appropriate target cell by binding to the rHuman T-cell receptor (CD4) and chemokine co-receptor CXCR4 (also called fusin) or CCR5 (chemokine C–C motif receptor 5).13, 14 Upon gp120 binding, gp41 undergoes a series of conformational changes to convert from native, non-fusogenic conformation to fusogenic conformation mediating fusion of the HIV membrane with the human cell membrane, thereby allowing introduction of the viral genome into the target cell.15, 16 The biomolecules involved in the HIV entry process can serve as targets for development of anti-HIV drugs to block these early steps of viral cycle life. Entry inhibitors are a new family of antiretrovirals presently represented only by one drug, T-20 (Enfuvirtide, Fuzeon^®) a peptidic drug targeting gp41.¹⁷ This synthetic peptide of 36 amino acid based on the sequence of the C-terminal heptad repeat regions (CHR) helix of gp41 was found to bind to the N-terminal heptad repeat regions (NHR) coiled coil.¹⁸ It prevents the peripheral attachment of the three CHR helices to the NHR coiled coil, thereby inhibiting the formation of the six-helix bundle and consequent fusion of the viral and cell membranes.19, 20 However, T-20 as a relatively long peptide suffers from two crucial limitations: lack of oral availability and high cost of production. Furthermore, T-20 is vulnerable to proteolytic digestion because it is composed of L-amino acids.¹⁶ As a result there is a considerable interest to develop small-molecules anti-HIV-1 compounds with a mechanism of action similar to that of C peptides but without the disadvantages of the peptidic drugs.

It was proposed that compounds binding to the gp41 NHR and CHR regions and blocking the six-helix bundle formation might have inhibitory activity on HIV mediated membrane fusion.²¹ Effectively, each of the grooves on the surface of the N-helix trimer has a deep hydrophobic pocket that accommodates three conserved hydrophobic residues in the gp41 CHR region, suggesting that this pocket is an attractive target for designing new class of anti-HIV-1 drugs.22, 23 Based on this information, several studies have developed a series of high-throughput screening assays, which have used for screening chemical libraries consisting of ‘drug-like’ compounds. Two small-molecules, ADS-J1 and XTT formazan, were identified and presented anti-HIV activity by docking into the gp41 pocket, thereby interfering with the fusion viral and cell membranes.24, 25, 26 More recently, two pyrrole derivatives, NB-2 and NB-64, were reported as novel HIV-1 fusion inhibitors at low micromolar levels, which may bind to the gp41 hydrophobic pocket via hydrophobic and ionic interactions and block the formation of the six-helix bundle.24, 27

NB-2 and NB-64 are ‘drug-like’ and were used by Xie et al.²⁸ as leads for designing more pyrrole derivatives. These new pyrrole derivatives were then synthesized and the inhibitory activities determined (data to be published). After this, we search to gain an insight into the binding mode and interactions of these compounds with HIV-1 gp41 and, consequently, to improve the development of more efficient fusion inhibitors. The applicability of QSAR/QSPR (Quantitative Structure–Activity Relationship/Quantitative Structure–Property Relationship) methodology to various problematic has been convincingly demonstrated in a series of publications.29, 30, 31 In this paper, we report the 2D- and 3D-QSAR analyses along with docking studies on 23 novel pyrrole derivatives as HIV-1 entry inhibitors. Moreover, the results obtained from QSAR analyses were superimposed on the gp41 active site and the main interactions were studied. These findings provide us very good advices for future structural modifications of this new class of entry inhibitors.

Section snippets

Data set preparation

The data set consists in 23 N-substituted pyrrole compounds listed in Table 1 which were synthesized²⁸ and evaluated for their inhibitory activity on HIV-1 replication by ELISA for measuring HIV-1 gag protein p24 as previously described.²⁷ Here, all these values are expressed in terms of −log(EC₅₀) where EC₅₀ represents the concentration of a compound resulting in 50 % inhibition of p24 production.

Since no structural information is available for the molecules of our data set, the molecular

Results and discussion

The experimental results cover a wide range of EC₅₀ from 0.69 μM to 371.24 μM giving us information useful to understand the different activity profiles of the molecules of our data set.

Conclusions

Here, we report the systematic 2D, 3D-QSAR and docking studies on pyrrole derivatives as HIV-1 gp41 inhibitors. The activity of the ligands was discussed by analyzing the physico-chemical meaning of the descriptors involved in the QSAR model. These descriptors could be essentially related to the shape (YZ shadow) and electron reactivity for a C atom concluding that an increase of the first property and a decrease of the last one are contributing for the activity. The consistency of the 2D-QSAR

Acknowledgments

We are grateful for the financial support from Fundação para a Ciência e a Tecnologia (Portugal) for the PhD fellowship SFRH/BD/22190/2005 to Cátia Teixeira, from the French Ministry of Research and Technology for the PhD fellowship to Joseph Rebehmed, from Ministry of Science and Technology in China (2006DFA3356 and 2006AA02Z319) to Lan Xie and the US NIH grant (RO1AZ46221) to Shibo Jiang.

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Molecular modeling studies of N-substituted pyrrole derivatives—Potential HIV-1 gp41 inhibitors

Abstract

Graphical abstract

Introduction

Section snippets

Data set preparation

Results and discussion

Conclusions

Acknowledgments

J. Clin. Virol.

J. Clin. Virol.

J. Biol. Chem.

J. Virol. Meth.

Cell

Biochem. Biophys. Res. Commun.

Dyes Pigments

Bioorg. Med. Chem.

Anal. Chim. Acta

Chemom. Intell. Lab. Syst.

Nat. Med.

Science (New York, NY)

JAMA

JAMA

J. Acquir. Immune Defic. Syndr.

AIDS (London, England)

AIDS (London, England)

Retrovirology

Annu. Rev. Immunol.

J. Cell Biol.