3D-QSAR研究揭示非核苷HIV-1 RT抑制剂的关键结构特征

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本文是一篇关于非核苷HIV-1逆转录酶抑制剂的3D-定量构效关系(QSAR)研究，着重于分子场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法的应用。研究对象是2-氨基-6-芳基磺酰基苯甲腈及其硫代和亚磺酰基衍生物，这些化合物作为HIV-1逆转录酶（RT）的非核苷抑制剂。作者首先通过对接模拟将这些抑制剂置于RT的活性位点，以探讨它们的理想结合模式和可能的构象。在分子建模过程中，研究人员利用了基于受体和配体的3D-QSAR技术，对比了不同的比对模式，确保了模型的交叉验证q值达到了高度可靠的标准，即CoMFA模型的q(2)为0.723，而CoMSIA模型的q(2)为0.760。这种高精度的模型有助于预测和理解药物与目标蛋白之间的相互作用，以及对抑制HIV-1活性至关重要的结构特征。研究发现，对于2-氨基-6-芳基磺酰基苯甲腈类抑制剂，关键的结构要求包括：B环的3位和5位需有大体积和疏水性的基团，这可能有利于增强与RT蛋白的相互作用；同时，A环的2-位与RT蛋白的Lys101残基形成氢键的供氢基团，也对抑制活性起到积极影响。这样的结构特性揭示了设计高效HIV-1 RT抑制剂时的关键参数，对于药物开发和优化具有重要的指导意义。这篇文章提供了一种定量的方法来理解和预测非核苷HIV-1 RT抑制剂的活性，为新药设计和现有药物的改造提供了科学依据。通过结合CoMFA、CoMSIA和对接模拟技术，研究者能够深入解析药物分子与靶蛋白的精细交互作用，为抗HIV药物研发领域带来了有价值的见解。

Receptor- and ligand-based 3D-QSAR study for a series of non-nucleoside

HIV-1 reverse transcriptase inhibitors

Rongjing Hu

a,b

, Florent Barbault

, Michel Delamar

, Ruisheng Zhang

a,c,

Department of Chemistry, Lanzhou University, Lanzhou, Gansu 730000, PR China

Interfaces, Traitement, Organisation et Dynamique des Systèmes (ITODYS), Paris-Diderot (Paris 7) University, CNRS UMR 7086, Bâtiment Lavoisier,

15 rue Jean Antoine de Baïf, 75205 Paris Cedex 13, France

School of Information Science and Engineering, Lanzhou University, Lanzhou, Gansu 730000, PR China

article info

Article history:

Received 3 October 2008

Revised 16 January 2009

Accepted 5 February 2009

Available online 8 February 2009

Keywords:

QSAR

CoMFA

CoMSIA

Docking

NNRTIs

HIV-1 reverse transcriptase

abstract

Molecular modeling of a series of HIV reverse transcriptase (RT) non-nucleoside inhibitors (2-amino-6-

arylsulfonylbenzonitriles and their thio and sulﬁnyl congeners) was carried out by comparative molecu-

lar ﬁeld analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches.

Docking simulations were employed to position the inhibitors into RT active site to determine the most

probable binding mode and most reliable conformations. The study was conducted using a complex

receptor-based and ligand-based alignment procedure and different alignment modes were studied to

obtain highly reliable and predictive CoMFA and CoMSIA models with cross-validated q

value of 0.723

and 0.760, respectively. Furthermore, the CoMFA and CoMSIA contour maps with the 3D structure of

the target (the binding site of RT) inlaid were obtained to better understand the interaction between

the RT protein and the inhibitors and the structural requirements for inhibitory activity against HIV-1.

We show that for 2-amino-6-arylsulfonylbenzonitriles inhibitors to have appreciable inhibitory activity,

bulky and hydrophobic groups in 3- and 5-position of the B ring are required. Moreover, H-bond donor

groups in 2-position of the A ring to build up H-bonding with the Lys101 residue of the RT protein are also

favorable to activity.

1. Introduction

The HIV type 1 reverse transcriptase (HIV-1 RT) is an essential

viral enzyme in HIV-1 virus. After HIV-1 infects a cell, RT plays a

central role in the viral replication cycle by catalyzing the conver-

sion of genomic single-stranded RNA into double-stranded proviral

DNA. The viral DNA is then integrated into the host chromosomal

DNA which then allows host cellular processes, such as transcrip-

tion and translation to reproduce the virus. HIV-1 RT is an asym-

metric heterodimer consisting of two polypeptides, p66 and p51.

Due to its importance, HIV-1 RT has been one of the major tar-

gets of the antiretroviral drugs. Nucleoside and non-nucleoside RT

inhibitors (NRTIs and NNRTIs) are two different categories:

2–4

the

former is an analogue of the natural deoxynucleotides that com-

pete with the natural deoxynucleotides for incorporation into the

growing viral DNA chain; the latter noncompetitively inhibits the

movement of protein domains of RT that are needed to carry out

the process of DNA synthesis. Nevirapine is a NNRTI used to treat

HIV-1 infection and AIDS, which was discovered by Hargrave

et al.

Later, different types of NNRTIs with similar interaction be-

tween inhibitors and RT protein have been discovered or de-

signed.

6,7

The high bioactivity and effectivity of nevirapine and

other inhibitors proved that RT is an important and signiﬁcant tar-

get to design anti-HIV drugs.

A series of NNRTIs (2-amino-6-arylsulfonylbenzonitriles and

their thio and sulﬁnyl congeners) (Table 1) were designed by Chan

et al.

Because of their high activity and low toxicity, researchers

have studied them in order to get more information about the

activity and to design more potential anti-HIV-1 drugs.

9–11

In the

present work, a receptor-guided and ligand-based three-dimen-

sional quantitative structure–activity relationship (3D-QSAR)

study was carried out for the ﬁrst time for this series of inhibitors.

Receptor-guided QSAR is only available when the 3D structures of

a target protein or its homologue bound to the active compound

have been experimentally solved. We thus performed a docking

study to search for reasonable conformations and alignments for

CoMFA and CoMSIA studies and gain an insight into the interaction

between ligands and RT protein.

CoMFA relates the bioactivity of inhibitors with their steric and

electrostatic ﬁelds sampled at grid points deﬁning a 3D box around

molecules.

CoMSIA is most commonly applied in drug discovery

doi:10.1016/j.bmc.2009.02.003

* Corresponding authors. Tel.: +33 1 57 27 54 32; fax: +33 1 57 27 72 63 (M.D.),

Tel.: +86 931 8914000 8421 (R.Z.).

E-mail addresses: michel.delamar@univ-paris-diderot.fr (M. Delamar),

zhangrs@lzu.edu.cn (R. Zhang).

Bioorganic & Medicinal Chemistry 17 (2009) 2400–2409

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

journal homepage: www.elsevier.com/locate/bmc

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