Accepted Manuscript The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors Noha A. Saleh PII: DOI: Reference:

S1386-1425(14)01542-X http://dx.doi.org/10.1016/j.saa.2014.10.045 SAA 12860

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Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Received Date: Revised Date: Accepted Date:

3 August 2014 28 September 2014 15 October 2014

Please cite this article as: N.A. Saleh, The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), doi: http://dx.doi.org/ 10.1016/j.saa.2014.10.045

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The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors Noha A. Saleh Biophysics Department, Faculty of Science, University of Cairo, Giza , Egypt

The inhibition of HIV-1 protease is considered as one of the most important targets for drug design and the deactivation of HIV-1. In the present work, the fullerene surface (C60) is modified by adding oxygen atoms as well as Hydroxymethylcarbonyl (HMC) groups to form 6 investigated fullerene derivative compounds. These compounds have one, two, three, four or five O atoms + HMC groups at different positions on phenyl ring. The effect of the repeating of these groups on the ability of suggested compounds to inhibit the HIV protease is studied by calculating both Quantitative Structure Activity Relationship (QSAR) properties and docking simulation. Based on the QSAR descriptors, the solubility and the hydrophilicity of studied fullerene derivatives increased with increasing the number of oxygen atoms + HMC groups in the compound. While docking calculations indicate that, the compound with two oxygen atoms + HMC groups could interact and binds with HIV-1 protease active site. This is could be attributed to the active site residues of HIV-1 protease are hydrophobic except the two aspartic acids. So that, the increase in the hydrophilicity and polarity of the compound is preventing and/or decreasing the hydrophobic interaction between the compound and HIV-1 protease active site. Keywords: Docking, Fullerene, HIV-1 protease inhibitors, Hydroxymethylcarbonyl group, PM3, QSAR.

Introduction Acquired Immune Deficiency Syndrome (AIDS) is considered the terminal stage of Human Immunodeficiency Virus (HIV) infections. HIV is one of the dreaded infectious diseases of the late 20th century, having claimed more than 25 million lives over the past three decades [1-5]. The most widely spread type of HIV is HIV-1 type [6]. There are two keys prevent the reducing the incidence of new infections. The first one is the reducing the number of people living with HIV who do not know their serologic status. The other is the reducing the time between infection and diagnosis 1

[7]. Many drugs are getting ineffective due to resistance offered by the mutationprone HIV. Hence, there is an urgent need for developing new drugs with greater potential [8]. Two factors are crucial for understanding the underlying principles of drug resistance. First, HIV has a very high reproduction rate. Secondly, the high error rate of the reverse transcriptase when transcribing viral RNA to DNA results in a large number of mutated forms of the virus being produced [9]. The three essential enzymes of HIV-1 virus are HIV-1 protease (PR), HIV-1 reverse transcriptase (RT), and HIV-1 integrase (IN) [8]. HIV-1 protease and HIV-1 reverse transcriptase are considered the important target sites for HIV-fighting drugs. [11, 12]. The HIV-1 protease can recognize Phe-Pro or Tyr-Pro sequences as the retrovirus-specific cleavage sites and its essential activity is the cleavage of the junctions between the gag and gag–pol polyproteins [12,13]. The HIV-1 protease is a homodimer with C2 symmetry. The homodimeric protein is composed of two chemically identical subunits of 99 amino acid subunits, each containing one catalytic aspartic acid Asp25 and Asp25'. The C2-symmetric active site is located at the dimer interface and each subunit contributes one catalytic aspartic acid residue present in a tripeptide sequence, Asp25, 25' -Thr26, 26' -Gly27, 27'. The protease subunit fold consists of a compact structure of β-strands with a short α-helix near the C-terminus [13-15]. There are two specific characters for HIV-1 protease. The first one, the cavity of HIV-1 protease active site is about 10 Å in diameter. The second one, all amino acids of HIV-1 protease active site are hydrophobic except two hydrophilic aspartic acids (Asp25 and Asp25') [16]. Due to these HIV-1 protease active site characters, the fullerene C60 is considered a good inhibitor of the activity of HIV-1 protease. This is because (a) the diameter of fullerene C60 close to the diameter of HIV-1 protease active site cavity. (b) The fullerene C60 is more stable and not easily degradable like as other fullerenes types. (c) Its hydrophobic surface provide strong van der Waals interaction between fullerene C60 and HIV-1 protease active site [16, 17]. There are many fullerene C60 derivatives studied to use as HIV-1 protease inhibitors [16-24]. In previous study the modified fullerene systems were investigated by utilizing both molecular modeling and QSAR descriptors [9, 24, 25]. These modified fullerene compounds had pyrrolidine ring to form fulleropyrrolidine in addition to O, S or Se atom and hydroxymethylcarbonyl (HMC) groups at para position on phenyl ring or at para and meta position on phenyl ring (Scheme 1). The compounds with O atoms indicated the best biological activity. In the present study, the O atom with HMC 2

group is repeated at different position on phenyl ring to investigate the effect of this repeatation on the ability of compound to act as HIV-1 protease inhibitor. This effect is studied by calculating the QSAR properties and docking simulation. Computational details The investigated compounds which are selected as a target for this study are built by HyperChem 7.5 program [26]. QSAR calculations The Quantitative Structure Activity Relationship (QSAR) is quantitative correlation between the physicochemical properties of molecules and their biological activities. The calculations of QSAR properties are performed using the HyperChem 7.5 program [26]. The geometries of the studied compounds are optimized at semiempirical quantum mechanical PM3 level of calculations [27], using the restricted Hartree–Fock (RHF) procedure [28]. The Polak–Ribier algorithm [29] is used for the optimization, with the termination condition being a root mean square (RMS) of < 0.001 kcal mol-1. The optimized structures are confirmed by calculating IR spectra of compounds at the same semi-empirical PM3 level to confirm that the obtained structures are corresponding to real structures not corresponding to transitions states. The QSAR calculated descriptors include total energy, heat of formation, dipole moment, hydration energy, log p, refractivity, surface area (grid) and volume. Docking calculations The docking molecular simulation is calculated by SCIGRESS 3.0 program [30]. The origin of HIV-1 protease which used for this calculation is the Protein Data Bank (PDB code: 4DJO) [31]. After preparing the protein structure by adding the hydrogen atoms, the optimized geometry of HIV-1 protease is calculated using MM3 force field which is better than the MM2 force field [32]. The conserved catalytic triad residues of HIV-1 protease active site Asp25 - Thr26 - Gly27 (for first monomer of HIV-1 protease) and Asp25' -Thr26' - Gly27' (for second monomer of HIV-1 protease) are selected as a group to be ready for docking calculation. By performing the genetic algorithm, the both FASTDOCK and PMF04 scoring function [33-36] are used to fit the ligand into the selected HIV protease active site residues. The optimization of best score docking systems is recalculated for docking systems at MM3 force field.

3

Result and discussion Building the model molecules In previous study of our research group, the calculated electronic and QSAR properties of some modified fullerene based systems were studied to act as HIV protease inhibitors. These suggested fullerenes based systems form two groups. The first group had one hydroxymethylcarbonyl group with polar atom O, S or Se (Scheme 1). The second group had two hydroxymethylcarbonyl groups with polar atom O, S or Se (Scheme 1). The final conclusion of this study that the oxygen compounds in the first and second groups are may be the most promising anti HIVprotease structures [9,24]. In the present study the oxygen compounds are modified to increase the solubility and reactivity of the suggested compounds. This modification occurred by adding one, two, three, four or five O atoms + hydroxymethylcarbonyl (HMC) groups at different positions on phenyl ring. According to this modification, there are 6 introduced compounds (a, b, c, d, e and f compound) (Scheme 2). The a compound has one HMC group at position 3 on phenyl ring. The b compound has two HMC groups at position 2 and 3 on phenyl ring. The c compound has three HMC groups at position 1, 2 and 3 on phenyl ring. The d compound has three HMC groups at position 2, 3 and 4 on phenyl ring. The e compound has four HMC groups at position 1, 2, 3 and 4 on phenyl ring. The f compound has five HMC groups at position 1, 2, 3, 4 and 5 on phenyl ring. The optimized geometries of studied compounds are calculated at semi-empirical PM3 level. The geometries of introduced optimized structure are represented in figure 1. To be insured that these geometries of studied compounds are real and in ground state, the partial charge of compounds are zero and the calculated IR spectra are performed at the same level of theory method. Now the suggested compounds are ready to be investigated its physical and biological properties. QSAR study Some QSAR descriptors of investigated compounds are calculated via PM3 level. These calculated descriptors represented in table 1 and include total energy, heat of formation, dipole moment, hydration energy, log p, refractivity, surface area (grid) and volume. The dipole moment values of a and b compounds are given from previous study [25]. The total energy of studied compounds varies from -324613.29 Kcal/mol for f compound to -218659.34 Kcal/mol for a compound. Generally, all 4

compound are stable and in ground state. This confirmed by the calculation of IR spectra for studied compounds. The increasing of the stability of compounds based on its total energy. If the total energy of the compound is the lowest, the compound will be most stable. So the most stable compound in this study is f compound (-324613.29 Kcal/mol). The

c and d compounds have similar total energy (-271643.1

Kcal/mol and -271645.8 Kcal/mol respectively). The change in enthalpy through the formation of one mole of a molecule from its elements in their natural and stable states, under standard conditions of one atmosphere at a given temperature called the heat of formation of the molecule [37]. From table 1 the a compound has the highest value of heat of formation (691.53 Kcal/mol), while the f compound has the lowest value of heat of formation (238.83 Kcal/mol). This indicates that the formation of one mole of f compound requires low change in enthalpy, while the a compound needs high change in enthalpy to form one mole of molecule. The heat of formation values are nearly the same for c and d compounds (458.4 Kcal/mol and 455.7 Kcal/mol respectively). The third QSAR descriptor which is listed in table 1 is the dipole moment. The dipole moment value of the compound gives indication about the reactivity of the compound. The compound with high dipole moment will be more reactive and the compound with low dipole moment will be less reactive with surrounding system. The dipole moment of suggested compound varies from 1.18 Debye to 5.08 Debye. The highest value of dipole moment in this study is 5.08 Debye for the f compound, while the lowest value is 1.18 Debye for a compound. The a and b compounds have the nearly values of dipole moment (1.18 Debye and 1.44 Debye respectively). Also the c and d compounds have the nearly values of dipole moment (2.64 Debye and 2.94 Debye respectively). The hydration energy is defined as the amount of energy released when a mole of the ion dissolves in a large amount of water forming an infinite dilute solution [9]. The hydration energy of studied compounds vary from -34.43 Kcal/mol for f compound to -8.45 Kcal/mol for

a

compound. From the hydration energy results in table 1, as the number of O atoms and HMC groups increase as the hydration energy will decrease. The hydration energy values are the same for the c and d compounds. The QSAR descriptor which describe the hydrophilicity of molecule is log p parameter.

The more soluble

compound and more hydrophilicity has low log p value. The less soluble compound and more hydrophobicity has high log p value. The log p value shown in table 1. The high negativity of log P values of the studied compounds indicate that the compounds 5

are high hydrophilic. The most soluble investigated compound in biological system is f compound (low log p value = -16.69). This is due to it has high number of polar atoms (five oxygen atoms and HMC groups) than the other studied compounds. The less soluble investigated compound in biological system is a compound (high log p value = -12.46). The c and d compounds have the same log P value (-14.57) because they are have the same number of oxygen atoms + HMC groups. The surface area (Grid) and volume of studied compound are represented in table 1. Logically, the surface area and volume increase as the number of HMC groups in the compound increase. So the a compound has the lowest surface area and volume (790Å2 and 1663.53Å3 respectively). While the f compound has the highest surface area and volume (1046.43Å2 and 2222.45Å3 respectively). The values of surface area and volume of c and d compounds are near to each other. Table 1 shows the refractivity values of suggested compounds. The refractivity depends on the volume and refractive index of the compound. So that the compound with high volume has high refractivity value and vice versa [38,39]. Due to the c and d compounds have nearly similar volume, they have the same value of refractivity. From calculated QSAR descriptors in this study, the f compound is the most stable compound (has lowest total energy value). It is also the most soluble in biological system (has lowest log p value) and reactive with the surrounding system (has highest dipole moment value), because it has high number of polar groups (oxygen atoms + HMC groups). There is question now, is f compound; the most soluble and reactive compound with surrounding system; will be binding and inhibit the protein such as HIV-1 protease? The docking calculation in the next part will be given almost a logical answer. Docking study To investigate the mechanism and mode of interaction between introduced compounds and protein and also to confirm the inhibition activity of the suggested compounds, the docking calculation of suggested compounds into the HIV-1 protease active site are performed. Due to all amino acids residues in HIV protease active site are hydrophobic residues except the two aspartic acid, the fullerene C60 of suggested compounds are oriented to the flaps of HIV-1 protease active site while the oxygen atoms with HMC groups are oriented to the two aspartic acids as shown in figure 2. 6

Figure 3 represents the docking systems and mode of interaction between investigated compounds (compounds a, b, c, d, e and f) and HIV protease. The a compound forms only one hydrogen bond (H-bond) with Arg8'. This H-bond forms between Arg8' and OH group of HMC of a compound. While b compound interacts with HIV-1 protease active site through four H-bonds. These bonds are formed with Ala28', Leu23' and Ile85'. Ala28' forms two H-bonds with OH group oh HMC at position 2. The HMC at position 3 forms two H-bonds, one with Leu23' through the OH group of HMC and the other with Ile85' through the O atom of HMC. The c and d compounds also form four H-bonds with HIV-1 protease. The c compound interacts with Asp29, Gly27, Thr26 and Leu24' of HIV-1 protease. Gly27 forms H-bond with OH group of HMC at position 1and Leu24' forms H-bond with OH group of HMC at position 2. Like the b compound, the HMC at position 3 forms two H-bonds, one with Thr26 through the OH group of HMC and the other with Asp29 through the O atom of HMC. The d compound interacts with HIV-1 protease through the forming of H-bonds with Thr26, Asp29 and Arg87 residues. Thr26 forms H-bond with O atom of HMC at position 2. Arg87 forms H-bond with O atom of HMC at position 3. While Asp29 forms two H-bonds with OH group of HMC at position 4. Although the compound c and d form four H-bonds, the mode of interaction with HIV-1 protease are different. On the other hand, e and f compounds docked into HIV protease active site through three H-bonds. In e compound, the three H-bonds are formed with Arg87', Gly27' and Thr26. The O atom of HMC at position 1 forms H-bond with Thr26. the HMC at position 3 forms two H-bonds, one with Arg87' through the O atom of HMC and the other with Gly27' through the OH group of HMC. The HMC groups at positions 2 and 4 dose not form any H-bonds with the HIV-1 protease. This insure that the increasing of the hydrophilicity through increase the HMC groups, the natural hydrophobic interaction with HIV-1 protease will decrease. Finally, the f compound forms H-bonds with Thr26, Thr26' and Arg8'. Arg8' forms H-bond with OH group of HMC at position 2. The OH group of HMC at position 5 forms two H-bonds, one with Thr26 and the other with Thr26'. The HMC groups at positions 1, 2 and 4 dose not form any H-bonds with the HIV-1 protease. Like the e compound, this insure that the effect of the high hydrophilicity on the docking interaction. The docking simulation systems are re-optimized at MM3 molecular mechanics force field. The total energy of docking system and docking score are 7

listed in table 2. The number of formed hydrogen bonds between studied compounds and HIV-1 protease are also represented in table 2. The highest total energy is 705.712 Kcal/mol for the docking system between f compound and HIV-1 protease. This value decreased with the decreasing the number of oxygen atoms + HMC groups until reach to the b compound which has the lowest total energy (-7.996 Kcal/mol). Then the total energy value increases again for a compound. The total energy of the docking system with c and d compounds are near to each other (375.1 Kcal/mol and 326.2 Kcal/mol respectively). This indicates that the c and d compounds have the same biological and inhibitory activity due to they have the same number of O atoms + HMC groups. In contrast, the docking score values increase as the number of oxygen atoms + HMC groups increase. As shown in figure 3 and table 2, the a compound forms only one H-bond in docking system. The b, c and d compounds form four H-bonds with HIV-1 protease. While e and f compounds form three Hbonds. Conclusion QSAR descriptors indicate that adding of repeated oxygen atoms + HMC groups to the suggested fullerene derivatives increases the biological activity of suggested compounds. The solubility, polarity reactivity and stability of studied compound increased with increasing the number of oxygen atoms + HMC groups. The c and d compounds have similar biological activity It could be concluded that any possible compounds with the same alternative number of oxygen atoms + HMC groups could be excluded because it is expected to give the similar biological activity. This ensures the effects of the repeating of oxygen atoms + HMC groups to the suggested compounds. According to the docking simulation and the special characters of HIV-1 protease active site, (a) the compound with low hydrophilicity show better interaction with HIV-1 protease than the compounds with high hydrophilicity. This is because the all amino acid residues in the cavity of HIV-1 protease active site are hydrophobic except the two hydrophilic aspartic acid residues. So that, the ligand-protein interaction based mainly on hydrophobic-hydrophobic interaction which is provided through fullerene C60. (b) Although the c and d compounds form four H-bonds, the mode of interaction with HIV-1 protease are different and the total energy of these 8

interaction systems are near to each other. This indicates that the c and d compounds have similar biological and inhibitory properties. (c) the b compound make good interaction with HIV-1 protease by forming four hydrogen bonds and this interaction system has the lowest total energy (-7.996 Kcal/mol). According to this study, the b compound has optimum polarity and solubility to act as HIV-1 protease inhibitor. In future, optimality of b compound should be confirmed experimentally and compared its binding modes with a number of HIV-1 protease mutants.

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10

X (HMC)

X (HMC)

X (HMC)

N

N

Scheme 1. The general structure of previous study suggested compounds. Where X atom is O, S or Se and HMC is the hydroxymethylcarbonyl group.

O (HMC)

O (HMC)

3

3

O (HMC) O (HMC)

3

4

2

4

2

4

5

1

5

1

5

N

a compound

N

b compound

1

O (HMC)

2 1 N

c compound

O (HMC)

O (HMC)

3

(HMC) O

O (HMC)

O (HMC) O (HMC)

3

(HMC) O

4

2

4

5

1

5

N

d compound

O (HMC)

4

2 1

3

(HMC) O

O (HMC)

(HMC) O

O (HMC)

2

5

1 N

N

e compound

f compound

Scheme 2. The general structure of investigated fullerene derivatives. Where HMC is the hydroxymethylcarbonyl group. a compound has one HMC group at position 3 on phenyl ring. b compound has two HMC groups at position 2 and 3 on phenyl ring. c compound has three HMC groups at position 1, 2 and 3 on phenyl ring. d compound has three HMC groups at position 2, 3 and 4 on phenyl ring. e compound has four HMC groups at position 1, 2, 3 and 4 on phenyl ring. f compound has five HMC groups at position 1, 2, 3, 4 and 5 on phenyl ring.

2

O (HMC)

a compound

b compound

c compound

d compound

e compound

f compound

Figure 1. The optimized geometries of investigated compounds at PM3 method. The cyan, white, red and blue balls represent the carbon, hydrogen, oxygen and nitrogen atoms respectively.

3

aps

Asp25'

Asp25

Figure 2. The general mode of interaction between the suggested compounds and HIV1 protease. The space filling residues are Asp25 (for first monomer of HIV-1 protease) and Asp25' (for second monomer of HIV-1 protease).

4

Ala28'

Ile85'

Arg8'Fl

Leu23'

a compound

b compound

Asp29 Thr26

Gly27 Thr26

Arg87 Leu24'

Asp29

c compound

d compound

Arg87'

Thr26'

Gly27'

Thr26

Thr26 Arg8'

e compound

f compound

Figure 3. The docking systems and mode of interaction between ligands and HIV-1 protease. The cylinder molecule is considered the studied compound and the ball & cylinder molecule is considered the amino acid residues of protein. The dashed lines represent the hydrogen bond. The symbol (') represent the residues in second monomer of HIV protease. 5

Table 1. Some calculated QSAR descriptors of suggested compounds at PM3 semiempirical level (note: The partial charge of all compounds equal to 0.0).

Total energy (Kcal/mol)

a b c d e f

-218659.34 -245156.82 -271643.15 -271645.77 -298129.99 -324613.29

Heat of formation (Kcal/mol) 691.53 569.36 458.35 455.73 346.82 238.83

Dipole moment (Debye) 1.179* 1.438* 2.643 2.939 3.680 5.078

Hydration energy (Kcal/mol) -8.450 -17.31 -23.18 -23.20 -27.51 -34.43

Log p

Refractivity (Å3)

-12.46 -13.52 -14.57 -14.57 -15.63 -16.69

285.07 297.90 310.74 310.74 323.57 336.40

Surface area (Grid) (Å2) 790.00 846.00 947.07 953.94 981.23 1046.43

* The dipole moment is calculated in this study not given from previous studies [25].

Table 2. The total energy, hydrogen bonds number and docking score of docking (interaction) systems via force field MM3 molecular mechanics method.

a b c d e f

Total energy (Kcal/mol) 65.94 -7.996 375.10 326.18 461.90 705.712

No. of H-bonds

Docking score

1 4 4 4 3 3

53550.128 68773.132 77272.257 116056.982 126283.129 403858.190

1

Volume (Å3) 1663.53 1800.92 1963.60 1973.49 2090.16 2222.45

Highlights

- Fullerene derivatives as HIV-1 protease inhibitors. - Quantitative Structure Activity Relationship (QSAR). - Docking calculations.

12

Graphical abstract        

The fullerene diameter is similar to the diameter of HIV-1 protease and form good hydrophobic interaction with the

Ile85'

Ala28

hydrophobic residues in HIV-1 protease. Unfortunately, the fullerene is insoluble in biological system. In this study some fullerene derivatives are modified to increase the solubility and inhibitory properties. These properties studied through QSAR and docking calculations. According to this study the fullerene derivative with two O atoms + HMC groups has good HIV-1 protease inhibitory properties. This

Leu2

result is benefit to improve the treatment of AIDS.

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The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors.

The inhibition of HIV-1 protease is considered as one of the most important targets for drug design and the deactivation of HIV-1. In the present work...
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