HIV抑制剂研究：分子动力学模拟揭示2-氨基-6-芳基磺酰基苯甲腈相互作用与结合亲和力

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该研究通过分子动力学模拟深入探讨了2-氨基-6-芳基磺酰基苯甲腈类似物作为HIV抑制剂的作用机制。研究涉及HIV-1逆转录酶（RT）与三种不同系列抑制剂的复合物，包括2-氨基-6-芳基磺酰基苄腈及其硫代和亚磺酰基衍生物。利用分子力学广义生表面积（MM-GBSA）方法评估了它们的结合自由能。在分子动力学模拟过程中，研究者在水环境下对RT及其与三种抑制剂的复合物进行了长时间的模拟，以观察稳定的状态和相互作用模式。通过分析MD轨迹，可以揭示RT与抑制剂间的动态相互作用，这些相互作用对于理解抑制剂如何阻止病毒复制至关重要。计算出的结合自由能与抑制剂的活性直接相关，反映了抑制剂与RT的结合亲和力。结果表明，不同的抑制剂与RT的相互作用方式存在差异，这主要体现在特定氨基酸残基的相互作用上。某些抑制剂表现出更强的结合能力，这主要是由于静电相互作用和溶剂化效应的增强。其中，最有效的抑制剂显示出更高的结合亲和力，这可能是其作为强效HIV抑制剂的原因。此外，研究还分析了各个残基对结合自由能的贡献以及氢键的作用。氢键在网络中的形成和断裂是影响抑制剂稳定性的重要因素。这些详细信息对于设计更有效的非核苷类逆转录酶抑制剂（NNRTIs）具有指导意义，可以为未来的药物研发提供结构基础。这项工作通过分子动力学模拟揭示了2-氨基-6-芳基磺酰基苯甲腈类似物与HIV-1逆转录酶的相互作用细节，为优化这些抑制剂的结构以提高其抗病毒效果提供了理论支持。这些发现对于对抗HIV感染的药物设计具有深远的影响，并可能推动新型抗病毒药物的发展。

Molecular Dynamics Simulations of

2-Amino-6-arylsulphonylbenzonitriles

Analogues as HIV Inhibitors: Interaction

Modes and Binding Free Energies

Rongjing Hu

1,2

, Florent Barbault

Franc¸ ois Maurel

, Michel Delamar

* and

Ruisheng Zhang

1,3,

Department of Chemistry, Lanzhou University, Lanzhou, Gansu

730000, China

Interfaces, Traitement, Organisation et Dynamique des Systmes

(ITODYS), Paris-Diderot (Paris 7) University, CNRS UMR 7086, 15 rue

Jean Antoine de Baf, 75205 Paris Cedex 13, France

School of Information Science and Engineering, Lanzhou University,

Lanzhou, Gansu 730000, China

*Corresponding authors: Michel Delamar, michel.delamar@univ-

paris-diderot.fr; Ruisheng Zhang, zhangrs@lzu.edu.cn

Molecular dynamics (MD) simulations in water

environment were carried out on the HIV-1 reverse

transcriptase (RT), and its complexes with one rep-

resentative of each of three series of inhibitors: 2-

amino-6-arylsulphonylbenzonitriles and their thio

and sulphinyl congeners. Molecular Mechanics

Generalized Born Surface Area (MM-GBSA) was

used to calculate the binding free energy based on

the obtained MD trajectories. Calculated energies

are correlated to activity. A comparison of interac-

tion modes, binding free energy, contributions of

the residues to the binding free energy and

H-bonds was carried out with the average struc-

tures. The results show that there exist different

interaction modes between RT and ligands and

different speciﬁc interactions with some residues.

The higher binding afﬁnity of the most potent

inhibitor in the series of molecules under study is

favoured by electrostatic interactions and solva-

tion contribution.

Key words: HIV-1 reverse transcriptase, molecular dynamics,

non-nucleoside reverse transcriptase inhibitors

Received 2 October 2009, revised 2 June 2010 and accepted for

publication 22 August 2010

The human immunodeficiency virus type 1 (HIV-1) reverse transcrip-

tase (RT) is one of the major targets for the treatment of AIDS.

This enzyme is responsible for the transition of the single-stranded

viral RNA into double-stranded proviral DNA, which is then

integrated into the host chromosome (1). RT has two activities. As

a DNA polymerase, it is able to copy either an RNA or DNA tem-

plate. It is responsible for the production of a double-stranded DNA

copy of the single-stranded RNA that is contained in the HIV-1 virus

particle

. This is extended by the polymerase function of RT to give

a DNA–RNA hybrid. RT also acts as a ribonuclease H (RNAse H)

which function is to cleave and degrade the template RNA after

DNA synthesis so that the newly made DNA can generate a second

DNA strand. It is also responsible for the integration of the duplex

DNA into the host cell chromosome. RT is a heterodimer protein

composed of two related chains: a 66-kD subunit (p66) and a 51-kD

subunit (p51) (1–5).

Because of its essential functions in the replication of the HIV virus,

RT is one of the major targets for the treatment of AIDS. Reverse

transcriptase inhibitors (RTIs) block reverse transcriptase's enzymatic

function and prevent completion of synthesis of the double-stranded

viral DNA, thus preventing HIV from multiplying. There are two

forms of RT inhibitors according their inhibitory mechanism: nucleo-

side (analogue) reverse transcriptase inhibitors (NRTIs), such as

zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T),

lamivudine (3TC), abacavir (ABC), and nucleotide (analogue) reverse

transcriptase inhibitors (NtRTIs), like PMEA (Adefovir) and PMPA

(Tenofovir) (6), which are acyclic nucleoside phosphonates, dideoxy

compounds lacking a 3¢ oxygen that cause DNA chain termination

when they are incorporated into a growing DNA strand. Non-nucle-

oside reverse transcriptase inhibitors (NNRTIs), such as nevirapine,

delavirdine, efavirenz, capravirine and dapivirine (TMC 125) (6), can

bind into a pocket between two beta-sheets of the p66 palm (7–9),

which is not far (about 10 ) from the polymerase active site. They

are not only spatially but also functionally associated with the poly-

merase active site; therefore, they prevent RT from converting the

single-stranded HIV RNA into double-stranded HIV DNA. Compared

with nucleoside RT inhibitors, NNRTIs are less toxic and more sta-

ble. Furthermore, their lower metabolism and clearance rates are

extra advantages. Nowadays, NNRTIs are also successfully used in

highly active antiretroviral therapy (HAART).

Chan et al. (10) designed a class of NNRTIs (2-amino-6-aryl-

sulphonylbenzonitriles analogues) that we study here. Some

518

Chem Biol Drug Des 2010; 76: 518–526

Research Article

ª 2010 John Wiley & Sons A/S

doi: 10.1111/j.1747-0285.2010.01028.x

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