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Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study a

b

b

Alexander M. Andrianov , Ivan A. Kashyn & Alexander V. Tuzikov a

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Street 5/2, 220141 Minsk, Republic of Belarus b

United Institute of Informatics Problems, National Academy of Sciences of Belarus, Surganov Street 6, 220012 Minsk, Republic of Belarus Published online: 20 Nov 2013.

To cite this article: Alexander M. Andrianov, Ivan A. Kashyn & Alexander V. Tuzikov (2014) Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study, Journal of Biomolecular Structure and Dynamics, 32:12, 1993-2004, DOI: 10.1080/07391102.2013.848825 To link to this article: http://dx.doi.org/10.1080/07391102.2013.848825

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Journal of Biomolecular Structure and Dynamics, 2014 Vol. 32, No. 12, 1993–2004, http://dx.doi.org/10.1080/07391102.2013.848825

Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study Alexander M. Andrianova*, Ivan A. Kashynb and Alexander V. Tuzikovb a

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Street 5/2, 220141 Minsk, Republic of Belarus; bUnited Institute of Informatics Problems, National Academy of Sciences of Belarus, Surganov Street 6, 220012 Minsk, Republic of Belarus Communicated by Ramaswamy H. Sarma

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(Received 4 July 2013; accepted 23 September 2013) A computer-aided search for novel anti-HIV-1 agents able to mimic the pharmacophore properties of broadly neutralizing antibody (bNAb) 3074 was carried out based on the analysis of X-ray complexes of this antibody Fab with the MN, UR29, and VI191 peptides from the V3 loop of the HIV envelope protein gp120. Using these empirical data, peptidomimetic candidates of bNAb 3074 were identified by a public, web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to the above V3 peptides were generated by molecular docking. The docking calculations identified four molecules exhibiting a high affinity to all of the V3 peptides. These molecules were selected as the most probable peptidomimetics of bNAb 3074. Finally, the stability of the complexes of these molecules with the MN, UR29, and VI191 V3 peptides was estimated by molecular dynamics and free energy simulations. Specific binding to the V3 loop was accomplished primarily by π–π interactions between the aromatic rings of the peptidomimetics and the conserved Phe-20 and/or Tyr-21 of the V3 immunogenic crown. In a mechanism similar to that of bNAb 3074, these compounds were found to block the tip of the V3 loop forming its invariant structural motif that contains residues critical for cell tropism. Based on these findings, the compounds selected are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics. Keywords: HIV-1; gp120 V3 loop; computer modeling; antibody 3074; peptidomimetics

Introduction The HIV-1 V3 loop plays a central role in the biology of the HIV-1 envelope glycoprotein gp120 as a principal target for neutralizing antibodies and as a major determinant in the switch from the nonsyncytium-inducing to the syncytium-inducing form of HIV-1 that is associated with accelerated disease progression (reviewed in the studies of Andrianov, 2011; Hartley, Klasse, Sattentau, & Moore, 2005; Sirois, Sing, & Chou, 2005; Sirois, Touaibia, Chou, & Roy, 2007). HIV-1 cell entry is mediated by the sequential interactions of gp120 with the receptor CD4 and a coreceptor, usually CCR5 or CXCR4, depending on the individual virion. The HIV-1 V3 loop is crucially involved in this process (Andrianov, 2011; Hartley, Klasse, Sattentau, & Moore, 2005; Sirois, Sing, & Chou, 2005; Sirois, Touaibia, Chou, & Roy, 2007). Findings on the structure, function, antigenicity, and immunogenicity of V3 provide evidence of its major influence on multiple functions of the gp120 protein, and indeed, on the entire functional HIV-1 Env complex, which consists of a trimeric structure comprising three gp120 surface glycoproteins, each noncovalently attached to one of subunits of the gp41 transmembrane glycoprotein (e.g. Wyatt & *Corresponding author. Email: [email protected] © 2013 Taylor & Francis

Sodroski, 1998). The early stage of viral entry involves binding of gp120 to the CD4 cell receptor causing a conformational change within gp120, resulting in the exposure of the bridging sheet and V3 loop, allowing it to bind to a chemokine coreceptor, either CCR5 or CXCR4, which is required for viral entry (Del Prete et al., 2010; Huang et al., 2007; Wu et al., 1996). The deletion of V3 loop renders the envelope unable to elicit neutralizing antibodies (Javaherian et al., 1989) and renders the noninfective virus (Freed, Myers, & Risser, 1991), thereby identifying the role of the V3 loop in the HIV-1 fusion. However, some mutants have been reported in which varying V3 truncations have nevertheless been enabled infectious virus (Del Prete et al., 2010). The HIV-1 V3 domain is usually composed of 35 amino acids, is rich in basic amino acids, and has aromatic amino acids for the aromatic stacking interaction with proteins (LaRosa et al., 1990; Tian, Lan, & Chen, 2002). The tip of V3 is highly immunogenic and contains neutralization epitopes for antibodies (Goudsmit et al., 1988; Rusche et al., 1988; Javaherian et al., 1989), although the epitopes can be inaccessible in the gp120 trimer on a virion of the HIV-1 primary isolates

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(Cavacini, Duval, Robinson, & Posner, 2002; Lusso et al., 2005) or HIV-1 recombinants with less positively charged V3 (Bou-Habib et al., 1994; Naganawa et al., 2008). It is known (e.g. Malenbaum et al., 2000) that V3 asparagines in positions 6 and 7 encode a highly conserved glycosylation site for specific binding to the Nlinked glycans, which modulates the interaction of the HIV-1 phenotypically diverse clades with CD4 and chemokine receptors and also serves to block access to the neutralization regions on gp120 of different isolates. The glycosylation is often at the base of V3, but N-glycans at other distant sites including the V1/V2 variable regions of gp120 have been found to affect V3 (e.g. Wolk & Schreiber, 2006). Interaction of the gp120 V1/V2 domain with the V3 loop has been recently shown to shield the HIV envelope trimer against cross-neutralizing antibodies (Liu et al., 2011; Rusert et al., 2011). The net charge of the V3 loop strongly relates to the phenotype of HIV-1. The V3 loops of CCR5 tropic HIV1s are usually less positively charged than those of CXCR4 tropic HIV-1s (Chesebro, Wehrly, Nishio, & Perryman, 1992; Fouchier et al., 1992; Milich, Margolin, & Swanstrom, 1993, 1997). An increase in the V3 net charge can convert CCR5 tropic viruses into CXCR4 tropic viruses (De Jong, De Ronde, Keulen, Tersmette, & Goudsmit, 1992; Shioda et al., 1994; Speck et al., 1997; Kato, Sato, & Takebe, 1999), and antibody resistant viruses into sensitive viruses (Bou-Habib et al., 1994; Naganawa et al., 2008). The HIV-1 gp120 V3 loop has been shown to act as an electrostatic modulator that influences the global structure and diversity of the interaction surface of the gp120 outer domain (Yokoyama, Naganawa, Yoshimura, Matsushita, & Sato, 2012). Thus, the V3 loop plays a key role in modulating biological and immunological phenotypes of HIV-1. Moreover, the V3 is reported to be the major determinant of HIV-1 sensitivity to neutralization by the soluble form of CD4 (Hwang, Boyle, Lyerly, & Cullen, 1992; Willey, Theodore, & Martin, 1994; Willey, Martin, & Peden, 1994), a recombinant protein that binds to the cleft of the gp120 core (Kwong et al., 1998). Finally, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer (Xiang et al., 2010). CD4 binding dismantles this element, altering the gp120/gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding. Although the V3 loop is a promising target for antiHIV-1 vaccine and drug design, its high sequence variability is a major complicating factor (LaRosa et al., 1990; Tian, Lan, & Chen, 2002). However, the latest findings obtained by comparison of the 3D V3 structures in various HIV-1 isolates and different environments make it

clear that the HIV-1 V3 loop forms at least three conserved structural motifs, which include residues crucial for cell tropism (Andrianov, 2011; Andrianov, Anishchenko, & Tuzikov, 2011; Andrianov et al., 2013). These data also amplify the observations of a work (Almond et al., 2010), whereby the most variable sequence positions in the crown of the V3 loop cluster to a small zone on the surface of one face of the V3 hairpin conformation, specifically demonstrating a superiority of conserved 3D structure in this highly sequence-variable region. It is assumed that these V3 sites represent potential HIV-1 vulnerable spots and, therefore, provide a blueprint for the design of novel antiviral agents that target the invariant elements of the HIV-1 V3 loop. There are a number of promising ligands for V3, such as immunophilin peptides and CD4-based peptidomimetics, glycolipids, porphyrins, etc., which exhibit a strong affinity to the HIV-1 gp120 V3 loop and, therefore, can serve as models for the design of efficient blockers of the invariant V3 segments by computational methods (reviewed in Andrianov, 2011). In light of these observations, the strategy to develop anti-HIV-1 vaccines and drugs based on coreceptor antagonists to efficiently mask these conserved segments of the V3 loop is highly challenging (Almond et al., 2010; Andrianov, 2011). The initial targeting the V3 loop for AIDS vaccine development originated from its tendency to elicit antibodies that are capable of neutralizing tissue cultured laboratory-adapted strains of HIV in animals (Goudsmit et al., 1988; Javaherian et al., 1989) and are present in the majority of the HIV-1-infected people (Vogel, Kurth, & Norley, 1994). Because of these observations, it seems highly likely that neutralizing antibodies to HIV-1 induced by a vaccine would provide benefit on exposure to the virus. There are, however, major challenges in the development of immunogens that induce bNAbs (reviewed in Hoxie, 2010; Walker & Burton, 2010). These challenges include the extraordinary genetic diversity of the virus, the relative inaccessibility of conserved epitopes that are targeted by bNAbs, the instability of the envelope glycoprotein (Env, the only known target for neutralizing antibodies), and the difficulties encountered in sustaining NAb titers following vaccination (Walker & Burton, 2010). Nevertheless, a large number of studies published in the last few years have described the presence of bNAbs in different cohorts (Binley et al., 2008; Gray et al., 2011; Piantadosi et al., 2009; Sather et al., 2009; Simek et al., 2009). According to these studies, neutralizing antibodies tend to increase in potency over time and broadly cross neutralizing responses, capable of recognizing heterologous HIV-1 variants, develop in a subset of individuals after primary infection. In some cases, the specificities of the antibodies conferring breadth have been mapped and are reactive with conserved envelope regions.

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Discovery of novel anti-HIV-1 agents by computer modeling Recent advances in analyzing humoral immunity have shown that bNAbs are produced in many HIVinfected individuals (Binley et al., 2008; Sather et al., 2009; Scheid et al., 2009), and these findings have provided hope that understanding the structure, specificity, and mechanism of their action will help to inform new approaches for vaccine design. In the context of discovering anti-HIV-1 bNAbs, studies aimed at the identification of chemical compounds that are able to mimic pharmacophore properties of these antibodies are of great interest. In this work, computer-aided search for novel anti-HIV-1 agents presenting potential peptidomimetics of bNAb 3074 (Burke et al., 2008; Gorny et al., 2006; Hioe et al., 2010) was carried out followed by evaluation of their potential inhibitory activity by molecular modeling. Anti-V3 monoclonal antibody 3074 was isolated from an individual living in Cameroon and the first paper describing it was published in 2006 (Gorny et al., 2006). This antibody presenting the HIV1 strain CRF02_AG (Gorny et al., 2006) displays broad neutralizing activity against multiple HIV-1 subtypes (Hioe et al., 2010). Structural characteristics of bNAb 3074 are given in a study of Burke and coauthors (Burke et al., 2008). The epitope targeted by bNAb 3074 was shown to be present in 87% of circulating strains, distributed nearly evenly among all subtypes (Swetnam, Shmelkov, Zolla-Pazner, & Cardozo, 2010). In other words, antibody 3074 targets an epitope that is nearly completely conserved among circulating HIV-1 strains, demonstrating the presence of an invariant structure hidden in the dynamic and sequence-variable V3 loop in gp120 (Swetnam, Shmelkov, Zolla-Pazner, & Cardozo, 2010). With the X-ray data (Jiang et al., 2010), antibody 3074 specifically binds to the HIV-1 V3 loop by π stacking of its aromatic residue PheH96 with the conserved Pro-16 of the V3 immunogenic tip. To reach the goal of this study, the following problems were solved: (i) the bNAb 3074 amino acid residues responsible for specific binding to the HIV-1 V3 loop were identified from the X-ray structures of this antibody Fab in the complexes with the MN, UR29, and VI191 V3 peptides (Jiang et al., 2010); (ii) using these data, an ensemble of peptidomimetic candidates of bNAb 3074 was generated by pepMMsMIMIC, which is a public, web-oriented virtual screening platform based on a multiconformers 3D-similarity search strategy (Floris, Masciocchi, Fanton, & Moro, 2011); (iii) the complexes of these compounds with the above V3 peptides were built by molecular docking and, based on their analysis, four molecules exhibiting a high affinity to V3 in the in silico studies were selected as the most probable peptidomimetics of bNAb 3074; (iv) stability of the complexes of these molecules with the MN, UR29, and VI191 V3 peptides was estimated by molecular dynamics and free binding energy simulations.

1995

As a result, the compounds selected were shown to present promising basic structures for the rational design of novel, potent and broad anti-HIV-1 drugs. Materials and methods The structural complexes of the bNAb 3074 Fab with the HIV-1 V3 loop peptides (Jiang et al., 2010) were taken from the Protein Data Bank (Bernstein et al., 1977; Berman et al., 2000). Interface analysis of these complexes was carried out by the BINANA program package (Durrant & McCammon, 2011), allowing one to identify the antibody residues critical for its interactions with V3. With this analysis, the antibody segment Arg-94-Asp-95-Phe-96-Gly-97-Glu-98-Tyr-99-His-100Tyr101 that greatly contributes to specific binding to the MN, UR29, and VI191 V3 peptides (Figure 1) was used for recognition of the potential peptidomimetics of bNAb 3074. To enlarge the input data-set for pepMMsMIMIC (Floris, Masciocchi, Fanton, & Moro, 2011), the above antibody site was divided into ten different fragments; at the same time, the residue TyrL49 of bNAb 3074 that assists PheH96 in π stacking with the conserved Pro-16 of V3 (Figure 1) (Jiang et al., 2010) was also included in the analyses. The final input data-set comprising different structural elements of the bNAb 3074 Fab is given in Table 1. The search for peptidomimetics was performed using all of the various options provided by the pepMMsMIMIC tools (Floris, Masciocchi, Fanton, & Moro, 2011) associated with the MMsINC database (http://mms.dsfarm. unipd.it/MMsINC.html) (Masciocchi et al., 2009). The database contains 17 million conformers calculated from 3.9 million commercially available chemicals. The tools offer five search procedures and different combinations of two scoring approaches, such as ultrafast shape recognition (Ballester & Richards, 2007) and pharmacophore fingerprints similarity (Karnachi & Kulkarni, 2006; Mason et al., 1999). The resulting ensemble of peptidomimetic candidates found in the MMsINC database was then evaluated by molecular docking to assess the efficacy of their binding to the MN, UR29, and VI191 V3 peptides. The 3D structures of the MN, UR29, and VI191 V3 peptides were extracted from their X-ray complexes with the bNAb 3074 Fab (Jiang et al., 2010) (codes 3MLX, 3MLY, and 3MLZ, respectively, in the Protein Data Bank; http://www.rcsb.org/pdb/) and used as static receptors for flexible ligand docking of the ensemble from the MMsINC database using the AutoDock VINA program (Trott & Olson, 2010). The hydrogen atoms were added to the X-ray V3 structures, and the protonation states were assigned using the H++ tools (Anandakrishnan, Aguilar, & Onufriev, 2012). The resulting nine supramolecular structures with the highest scores against each V3 peptide were analyzed to select the compounds

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Figure 1. Structural complexes of the bNAb 3074 Fab with the MN (a), UR29 (b) and VI191 (c) V3 peptides (Jiang et al., 2010). The antibody residues playing a key role in specific binding to the target peptides are shown. The peptide amino acids are numbered in line with their positions in the V3 sequence. H-bonds are denoted by dotted lines.

that specifically and effectively interact with all of the three target peptides. The selection criteria included similar values of the AutoDock VINA scoring function and similarity of the docked structures. The selected

complexes were exposed to energy refinement by simulated annealing (a method of global optimization of molecular systems) (Kirkpatrick, Gelatt, & Vecchi, 1983). Simulated annealing with AMBER 11 (Case et al., 2010)

Discovery of novel anti-HIV-1 agents by computer modeling Table 1. Input data-set used for the retrieval of the bNAb 3074 peptidomimetics in the MMsINC database. N

Input data-seta

Arg H94(S) AspH95(S) PheH96(S) GlyH97(CN) GluH98(S) TyrH99(CSN) HisH100(S) Tyr H101(S) 2 AspH95(S) PheH96(S) GlyH97(CN) GluH98(S) TyrH99(CSN) HisH100(S) 3 PheH96(S) GlyH97(CN) GluH98(S) TyrH99(S) HisH100(S) 4 PheH96(S) GlyH97(CN) GluH98(S) TyrH99(S) HisH100(S) TyrL49 (S) 5 PheH96 (S) GlyH97 (CN) GluH98 (S) TyrH99 (CSN) 6 PheH96 (S) GlyH97 (CN) GluH98 (S) TyrH99 (CSN) HisH100 (S) 7 PheH96 (S) GlyH97 (CN) GluH98 (S) TyrH99 (CSN) TyrL49 (S) 8 AspH95 (S) PheH96 (S) GlyH97 (CN) GluH98 (S) TyrH99 (S) HisH100 (S) 9 PheH96 (S) GlyH97 (CN) GluH98 (S) TyrH99 (S) TyrL49 (S) 10 AspH95 (S) PheH96 (S) GlyH97(CN) GluH98 (S) TyrH99 (CSN) TyrL49(S) 11 PheH96 (S) GlyH97 (CN) GluH98(S) TyrH99 (CSN) TyrL49 (CSN)

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1

a

The fragments of amino acid residues used in the input data-set are indicated in round brackets: letters S, N, and C respectively their side chain, N and C terminus.

was carried out by the Amber force field (parameter set ff10) in explicit solvent. The ligand parameters were obtained with the generalized Amber force field (GAFF) approach (Wang, Wolf, Caldwell, Kollmann, & Case, 2004). When annealing, the structures were heated to 500 K within 250 ps followed by 50 ps molecular dynamics trajectory production at isothermal conditions. Later, the structures were gradually cooled to 0 K within 700 ps; the aggregate annealing time was 1.0 ns. To solve the motion equations, the standard leapfrog algorithm (Case et al., 2010) with 0.5 fs time step was used at the stages of heating and high-temperature dynamics; Table 2.

at the cooling stage, this parameter was 1.0 fs. The temperature control was implemented by the Langevin thermostat (Case et al., 2010) with 10 ps−1 collision frequency. The lowest energy complexes observed after simulated annealing were selected for additional structural analysis and molecular dynamics (MD) simulations, which were carried out by the Amber 11 computer package using the Amber ff10 force field (Case et al., 2010). The selected structures from the simulated annealing were each placed in a truncated octahedron box with walls at least 10 Å from the nearest structural atoms, filled with TIP3P water (Jorgensen et al., 1983) as an explicit solvent, and subjected to periodic boundary conditions. The system was prepared for MD simulation by 500 steps of steepest descent followed by 1000 steps of conjugate gradient energy minimization. The following convergence criterion for the energy gradient was used: minimization halted when the root-mean-square of the Cartesian elements of the gradient was less than 10−4 kcal/mole-Å (Case et al., 2010). The atoms of the peptide assembly were then fixed by an additional harmonic potential with the force constant equal to 1.0 kcal/ mol and then heated from 0 to 310 K over 1 ns using a constant volume of the unit cell. Additional equilibration was performed over 1 ns by setting the system pressure to 1.0 atm and by using a weak coupling of the system temperature to a 310 K bath (Berendsen et al., 1984) with a 2.0 ps characteristic time. Finally, the constraints on the peptide assembly were removed, and the system was equilibrated again at 310 K over 2 ns under constant volume conditions. After equilibration, a normal MD simulation generated 30 ns trajectories for each peptide assembly using a Langevin thermostat (Case et al., 2010) with collision frequency 2.0 ps−1, a nonbonded cut-off distance of 8 Å, and a simple leapfrog integrator (Case

Chemical compounds, the most promising peptidomimetics of bNAb 3074a.

Compound code

Systematic name

MMs02389422 N-(5-{[5-(Benzoylamino)-9,10-dioxo-9,10-dihydro2-anthracenyl]amino}-9,10-dioxo-9,10-dihydro-1anthracenyl)benzamide MMs01094745 3,5-Bis[1,3-dioxo-5-(4-oxo-4H-3,1-benzoxazin2-yl)-1,3-dihydro-2H-isoindol-2-yl]benzoic acid MMs02387687 N-(4-{[5-(Benzoylamino)-9,10-dioxo-9,10-dihydro1-anthracenyl]amino}-9,10-dioxo-9,10-dihydro-1anthracenyl)benzamide MMs02384293 N,N’-[Iminobis(9,10-dioxo-9,10-dihydroanthracene5,1-diyl)]dibenzamide а

Number of H-bond donors

Number of H-bond acceptors

7.49

3

6

C39H18N4O10 702.581

5.48

2

10

C42H25N3O6

667.677

7.49

3

6

C42H25N3O6

667.677

7.49

3

6

Chemical formula C42H25N3O6

The information given is taken from the MMsINC database (Masciocchi et al., 2009). LogP denotes the compound lipophilicity.

b

1997

Molecular mass (Da)

LogPb

667.677

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et al., 2010) with a 2.0 fs time step and hydrogen atoms constrained by the SHAKE algorithm (Ryckaert, Ciccotti, & Berendsen, 1977). Electrostatic interactions were calculated at every step with the particle-mesh Ewald method (Essmann et al., 1995), short-range repulsive and attractive dispersion interactions were simultaneously described by a Lennard–Jones potential. The free energy of binding was used as a measure of conformational stability of the complexes of interest and was calculated by the MM-PB/SA procedure (Massova & Kollman, 1999) in AMBER. The polar solvation energies were computed in continuum solvent using Poisson–Boltzmann and ionic force of 0.1. The nonpolar terms were estimated using solvent accessible surface areas (Lindorff-Larsen et al., 2010). About 500 snapshots were selected from the last 25 ns, by keeping the snapshots every 50 ps. All calculations were run on the SKIF-UIIP computer cluster (Ablameyko et al., 2005).

Results and discussion

Figure 2. compounds 3074. The (Masciocchi

Two-dimensional structures of the chemical presenting potential peptidomimetics of bNAb molecule codes in the MMsINC database et al., 2009) are given.

As noted earlier, analysis of the bNAb 3074 Fab complexes with the V3 peptides shows that a key role in the binding belongs to the antibody H chain octapeptide,

which includes PheH96 participating in π–π interactions with the conserved Pro of V3 (Figure 1) (Jiang et al.,

Table 3. Intermolecular interactions appearing in the best energy complexes of the MMs02389422, MMs01094745, MMs02387687, and MMs02384293 compounds with the MN, UR29, and VI191 V3 peptidesa.

Compound (ligand)

V3 peptide (receptor)

MMs02389422

MN

MMs01094745 MMs02387687 MMs02384293 MMs02389422

UR29

MMs01094745 MMs02387687 MMs02384293 MMs02389422 MMs01094745 MMs02387687 MMs02384293

VI191

Types of interaction H-bond O1 O3 O7 O2

… … … …

b

π stackingc

HN(Ile-12) HN(Arg-11) HN(Thr-23) HO*(Thr-22)

O6 … HN(Tyr-21) O5 … HN(Tyr-21) O2 … HN*(Arg-15) O3 … HN*(Arg-15) O1 … HN*(Gln-18) O4H … N*(Arg-15) N1H … N*(Gln-18) N1 … HN*(Gln-18) O4 … HO*(Ser-11) N1H … N*(Gln-18) N1 … HN*(Gln-18) O4 … HO(Ser-11) N3H … O(Arg-18) N4 … HN(Ala-19) N1H … O(Ala-19) N1H … O(Ala-19)

T stackingc

Cation-π interactionc

6⋯Phe-20 7⋯Phe-20 6⋯Tyr-21 7⋯Tyr-21 1⋯Tyr-21 8⋯Tyr-21

6⋯Phe-20 3⋯Phe-20 8⋯Phe-20 3⋯Phe-20

5⋯Arg-18 4⋯Lys-10

1⋯Phe-20 2⋯Phe-20 3 ⋯Phe-20 2⋯Phe-20 3⋯Phe-20 5⋯Phe-20 3⋯Phe-20 3⋯Phe-20 4⋯Phe-20 2⋯Phe-20 3⋯Phe-20

a Intermolecular interactions were analyzed by the BINANA program (Durrant & McCammon, 2011). To identify π–π interactions, this program uses geometric criteria, including distances between aromatic rings as well as their spatial orientation (for details see Durrant & McCammon, 2011). b Donors and acceptors of the H-bonds relating to the ligands head a list; later, the corresponding functional groups of the V3 amino acids are shown. Atoms or groups of the peptide side chains are marked by asterisks. The peptide residues are numbered in line with their positions in the V3 aminoacid sequence. Subscripts of oxygen and nitrogen atoms coincide with their numbering given in Figure 2. c The peptidomimetic ring numbers (Figure 2) and the V3 peptide residues are denoted.

1999

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Discovery of novel anti-HIV-1 agents by computer modeling

Figure 3. Structural complexes of MMs01094745 with the MN (a), UR29 (b), and VI191 (c) V3 peptides. The peptide amino acids are numbered according to their positions in the V3 sequence. H-bonds are denoted by dotted lines.

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Table 4. Mean values of free binding energy < ΔG > for the complexes of the bNAb 3074 peptidomimetics with the HIV-1 V3 peptides and their standard deviations ΔGSTD. V3 peptide

Peptidomimetic

kcal/mol

ΔGSTD kcal/mol

MN

MMs02389422 MMs01094745 MMs02387687 MMs02384293 MMs02389422 MMs01094745 MMs02387687 MMs02384293 MMs02389422 MMs01094745 MMs02387687 MMs02384293

−22.7 −19.2 −21.5 −22.9 −19.4 −18.2 −24.3 −15.9 −25.1 −14.1 −26.2 −18.4

4.5 6.1 4.0 8.6 3.2 3.5 3.2 3.5 3.3 2.9 4.7 6.0

UR29

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VI191

2010). Using this octapeptide (Table 1), the pepMMsMIMIC tools identified 2039 peptidomimetic candidates from the MMsINC database. Four of these compounds were found in common among the ten top-scoring hits from molecular docking, which suggests that these molecules should specifically and effectively interact with the V3 peptides from diverse viral isolates. Brief information on these compounds is cited in Table 2, and their 2D structures derived from MMsINC (Masciocchi et al., 2009) are shown in Figure 2, which shows that the backbones of the four molecules are composed of aromatic rings imitating the pharmacophore properties of amino acids with π-conjugated side chains that are so important in the bNAb 3074 Fab (Figure 1). Analysis of the docked models of the complexes of the MMs02389422, MMs01094745, MMs02387687, and MMs02384293 compounds with the V3 peptides indicates (Table 3) that specific π–π interactions between the ligands and the target peptides are typical for all these supramolecular structures. At the same time, the ligand aromatic rings generally display T-stacking with the side chain of the V3 conserved Phe-20, except for the complex of MMs01094745 with the MN-V3 peptide, where the invariant Tyr-21 (LaRosa et al., 1990; Tian, Lan, & Chen, 2002) is used by V3 for π–π interactions with aromatic rings of this compound. For the MN and UR29 peptides, Tyr-21 participates in π stacking with MMs02389422 and MMs02387687 (Table 3). Along with π–π interactions, intermolecular H-bonds are also essential for energy stabilization of the complexes of interest (Table 3). As an example, Figure 3 shows the best energy complexes of the MMs01094745 compound with the MN, UR29, and VI191 V3 peptides. Inspection of these complexes illustrates that ligand binding to the target peptides leads to blocking of the tip of the V3 immunogenic crown that is critical for the recognition of

CCR5 (Basmaciogullari et al., 2002; Cormier & Dragic, 2002; Cormier, Tran, Yukhayeva, Olson, & Dragic, 2001; Hoffman et al., 1999; Huang et al., 2007; Hu et al., 2000; Shimizu et al., 1999). In particular, interactions of the V3 peptides with MMs01094745 result in masking a core sequence Gly-15–Pro-16–Gly17-Arg/Gln-18 of the V3 loop (Figure 3) involved in cell tropism. It is known that substitution for Pro-16 by alanine greatly influences the HIV-1 infectivity and immunogenicity (Ivanoff et al., 1991; Takeuchi et al., 1991), and single substitutions of Gly-15, Gly-17, or Arg-18 may be lethal for the virus infectivity and its capacity for syncytium formation (Ivanoff et al., 1992; Grimaila et al., 1992). These data testifying to significance of Gly-Pro-Gly-Arg/Gln for a coreceptor usage are also confirmed by the studies of the viral mutants lacking in this site of gp120 (Grimaila et al., 1992). In the complex of MMs01094745 with UR29 (Figure 3(b)), Pro-16 of V3 is remote from the ligand, which is likely caused by local structural rearrangements of this V3 peptide that may be initiated by rare substitutions for Gly-15 and Gly-17 of the V3 tip by arginine. Nevertheless, Arg-15 and Gln-18 of UR29 form three H-bonds with MMs01094745 (Figure 3(b) and Table 3). Examining the complexes of MMs02389422, MMs02387687, and MMs02384293 with the V3 peptides shows (Table 3) that, as with MMs01094745, the majority of the amino acid residues that are used by V3 for the formation of the supramolecular structures fall into its central part, residues 15–20. These data are of interest in connection with studies (Andrianov, 2011; Andrianov, Anishchenko, & Tuzikov, 2011; Andrianov et al., 2013), whereby this site of gp120 makes the conserved structural motif and may therefore serve as the promising target for the design of novel broad anti-HIV1 agents. The molecular docking simulations demonstrated that the compounds found by pepMMsMIMIC exhibit the close mode of specific binding to the MN, UR29 и VI191 V3 peptides, which originates from π–π interactions of aromatic rings of the bNAb 3074 peptidomimetics with the V3 conserved Phe-20 and/or Tyr-21. As mentioned previously, this is similar to the way bNAb 3074 specifically binds to the V3 loop via π stacking of its PheH96 with Pro-16 of V3 (Figure 1) (Jiang et al., 2010). The MD simulations support the docking results. The majority of the MD trajectories show the structures keeping the intermolecular H-bonds and π–π interactions that appear in the docked models (Table 3). The complexes generated by molecular docking are energetically stable within the 25 ns time domain, which is validated by the mean values of free binding energy and their standard deviations (Table 4). It is likely that the time

Discovery of novel anti-HIV-1 agents by computer modeling

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domain used in the MD simulations is insufficient to scan all possible structural variants for the complexes of MMs02389422, MMs01094745, MMs02387687, and MMs02384293 with the MN, UR29, and VI191 V3 peptides. However, the findings of these calculations, which were obtained based on twelve starting points presenting the static models of the complexes of four different compounds with three diverse target peptides, clearly testify to their similar dynamic characteristics in all of the cases of interest and allow one to believe that our MD simulations adequately describe the general dynamic features of the analyzed supramolecular structures.

Conclusions Comprehensive analysis of the static and dynamic models for the complexes of MMs02389422, MMs01094745, MMs02387687, and MMs02384293 with the MN, UR29 and VI191 V3 peptides points to specific and efficient interactions between these compounds and the HIV-1 gp120 V3 loop. At the same time, π–π interactions between aromatic rings of the peptidomimetic candidates and the conserved Phe-20 and/or Tyr-21 of the V3 central region play a key role in the binding. Similarly to bNAb 3074 (Figure 1), the formation of the complexes results in blocking of the V3 tip making the invariant structural motif that contains residues crucial for cell tropism (Andrianov, 2011; Andrianov, Anishchenko, & Tuzikov, 2011; Andrianov et al., 2013; Almond et al., 2010). According to the MD data, the complexes of interest do not go through substantial rearrangements during the MD simulations, exhibiting the low values of free energy of their formation (Table 4). Thus, the data of molecular modeling clearly suggest that the chemical compounds given in Figure 2 are able to neutralize different HIV-1 modifications and, therefore, should be subject to testing for anti-HIV-1 activity against various viral isolates. Since the X-ray data on the complexes of bNAb 3074 with the MN, UR29, and VI191 V3 peptides were published three years ago (Jiang et al., 2010), new files describing supramolecular structures of bNAbs Fabs associated with the HIV-1 conserved epitopes from different regions of the virus envelope were deposited in the Protein Data Bank (reviewed in Hoxie, 2010; Kwong, Mascola, & Nabel, 2011; McCoy & Weiss, 2013; Walker & Burton, 2010; view also at http://www. rcsb.org/pdb/). Obviously, computer-aided search for peptidomimetics of these antibodies by the above approach may bring to discovery of novel anti-HIV-1 agents with different mechanisms of therapeutic action exposing promising starting points for the development of potent and broad anti-AIDS drugs.

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Acknowledgments The authors thank Dr Darrell Hurt (NIH/NIAID) for careful reading and correcting the manuscript.

Funding This study was supported by grant from the Belarusian Foundation for Basic Research (project X12-022).

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Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study.

A computer-aided search for novel anti-HIV-1 agents able to mimic the pharmacophore properties of broadly neutralizing antibody (bNAb) 3074 was carrie...
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