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European Journal of Applied Sciences – Vol. 11, No. 6

Publication Date: December 25, 2023

DOI:10.14738/aivp.116.15904

Ferrari, I. V., & Ravagnan, G. (2023). Polydatin Against HIV Proteases. European Journal of Applied Sciences, Vol - 11(6). 282-293.

Services for Science and Education – United Kingdom

Polydatin Against HIV Proteases

Ivan Vito Ferrari

Institute of Clinical Physiology,

National Research Council, Via Aurelia Sud, 54100 Massa, Italy

Giampietro Ravagnan

Institute of Translational Pharmacology,

Consiglio Nazionale delle Ricerche, Rome, Italy

ABSTRACT

Introduction: HIV (human immunodeficiency virus) is a virus that attacks and

destroys one type of white blood cell, in particular, the CD4 lymphocytes, which are

responsible for the body's immune response. This weakens the immune system to

such an extent that it can no longer fight other viruses, bacteria, protozoa, fungi, and

tumors. Methods: We investigated the potential biological role of the natural

compound Polydatin (or piceid) using SwissDock, a web service to predict the

molecular interactions that can occur between a target protein and a small

molecule. Discussion: For the first time, we have investigated the role of polydatin

against HIV-1 protease and HIV-2 protease through a computational approach by

comparing their estimated ΔG values (kcal/mol) and the nature of the interactions

between the residues in the catalytic center of the HIV proteases. Conclusion: From

these simulations, Polydatin has excellent physical properties and an excellent

estimated ΔG value (kcal/mol) of about -9.9 kcal/mol against HIV-2 protease and

ΔG value (kcal/mol) of about -9.5 kcal/mol against HIV-1 protease. In addition,

Polydatin was able to bind to two key amino acids of the catalytic triad sequence

common to asparagine proteases (Asp25 and Gly27)

Keywords: Polydatin, HIV, Docking method, Swiss Dock Server

INTRODUCTION

The human immunodeficiency virus (HIV), which causes AIDS, is spread differently from

country to country [1-4]. According to the World Health Organisation (WHO), around 40.1

million people have died from HIV/AIDS by 2021 and around 38.4 million people are infected

with HIV worldwide [5]. This study investigates the relationship between HIV-1 Protease and

or HIV-2 Protease with the natural compound Polydatin (called Piceid), a natural precursor and

glycoside form of resveratrol with a monocrystalline structure [6]. Fig.1 shows its 2D and its

3D crystal structure. It is isolated from the bark of Picea sitchensis or Polygonum cuspidatum,

polydatin may be detected in grape, peanut, hop cones, red wines, hop pellets, cocoa-containing

products, chocolate products, and many daily diets [6]. The detailed structure of the HIV

protease has been used to design effective drugs for the treatment of AIDS [1;3]. HIV-2 is a virus

of the Retroviridae family, Lentivirus genus; it represents one of the two HIV serotypes,

together with the much more widespread HIV-1, which is responsible for the HIV pandemic

worldwide. HIV-2, on the other hand, has a more limited geographic spread [7]. Fig. 2 shows

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Ferrari, I. V., & Ravagnan, G. (2023). Polydatin Against HIV Proteases. European Journal of Applied Sciences, Vol - 11(6). 282-293

URL: http://dx.doi.org/10.14738/aivp.116.15904

the comparison of the 3D crystal structures of HIV-1 protease and HIV-2 protease with their

crystal inhibitors in the active site. The focus of this work was to evaluate, using computational

methods, the potential biological role of these HIV proteases with polydatin. We chose to

investigate Piceid because many scientific articles report not only that it has low side effects [6]

compared to other natural substances but also because it has different biological properties,

for example, antioxidant [8], anti-inflammatory [9], and anticancer properties [10]. In addition,

polydatin has powerful anti-free radical activity [8], and it reduces oxidative stress on cells and

tissues [11].

Fig-1: Comparison of 2D Crystal structure and 3D structure of Polydatin The figure was

reproduced by Drug Bank Database and UCSF Chimera program.

Fig-2: 3D Crystal structures of HIV-1 protease and HIV-2 protease with their crystal inhibitor in

the Active site. The figure was reproduced by UCSF Chimera program.

Crystal structures were taken by Protein Data Bank (PDB code: 1hvk and PDB code: 1hii).

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European Journal of Applied Sciences (EJAS) Vol. 11, Issue 6, December-2023

MATERIAL AND METHODS

SwissDock, a web service for predicting molecular interactions that might occur between a

target protein and a small molecule [12], was used to predict the potential role of Polydatin

with HIV-1 protease and HIV-2 protease. SwissDock and S3DB are developed by Aurélien

Grosdidier, Vincent Zoete and Olivier Michielin, from the Molecular Modeling Group of

the Swiss Institute of Bioinformatics in Lausanne, Switzerland [12]. SwissDock is based on the

docking software EADock DSS, whose algorithm consists of the following steps [12]:

• many binding modes are generated either in a box (local docking) or in the vicinity of all

target cavities (blind docking).

• simultaneously, their CHARMM energies are estimated on a grid.

• the binding modes with the most favorable energies are evaluated with FACTS, and

clustered.

• the most favorable clusters can be visualized online and downloaded on your computer.

In this wok, 3D Crystal structures of HIV-1 protease and HIV-2 protease with their crystal

inhibitor in the Active site and saved in PDB format. Crystal structures were taken by Protein

Data Bank (PDB code: 1hvk and PDB code: 1hii). Polydatin was downloaded from Pubchem

Database and saved in SDF format.

RESULTS AND DISCUSSION

For the first time, this theoretical study focused on the relation between HIV-1 protease and

HIV-2 protease with a natural compound named polydatin (or Piceid, 3,4,5-trihydroxystilbene- 3-beta-monoglucoside). Several papers have reported the excellent biological role of this

compound in the literature [8,11]. However, there are few recent works that have studied the

role of polydatin in the HIV virus [13, 14]. Heredia et al. 2020 reported synergistic inhibition of

HIV-1 in activated and remaining peripheral blood mononuclear cells, monocyte-derived

macrophages, and selected drug-resistant isolates with nucleoside analogs combined with a

natural product, resveratrol [13]. Pflieger et al. (2013 studied natural stilbenoids isolated from

grapevine exhibiting inhibitory effects against HIV-1 integration and eukaryote MOS1

transposase in vitro activities [14]. Our main contribution was to investigate polydatin by

molecular docking with HIV-1 protease and HIV-2 protease, respectively. The methods were

performed by SwissDock Server, a web service for predicting molecular interactions that might

occur between a target protein and a small molecule [12]

Table 1. shows the comparison docking results evaluated by SwissDock. As can be seen from

this Table, Polydatin has been shown to have a higher estimated ΔG score than the ligand crystal

both in the case of HIV-2 protease and HIV-1 : ( Estimated ΔG of Polydatin was -9.89 kcal/mol

VS Estimated ΔG of Crystal Ligand C20 [ACETYL-NH-VAL-CYCLOHEXYL-CH2[NCH2CHOH]CH2-

BENZYL-VAL-NH-ACETYL) was -12.14 kcal/mol, when they binds in the acitive site of HIV-2,

while Estimated ΔG of Polydatin was -9.47 kcal/mol VS Estimated ΔG of Crystal ligand A79 ( N-

{1-BENZYL-(2S,3S)-2,3-DIHYDROXY-4-[3-METHYL-2-(3-METHYL-3-PYRIDIN-2-YLMETHYL- UREIDO)-BUTYRYLAMINO]-5-PHENYL-PENTYL}-3-METHYL-2-(3-METHYL-3-PYRIDIN-2-

YLMETHYL-UREIDO)-BUTYRAMIDE) was -12.54 kcal/mol, when they binds in the acitive site

of HIV-1 protease. However, a very important aspect that we noticed was the binding ability of

Polydatin when it binds to HIV-1 protease or HIV-2 protease is not the same.