Docking and Molecular Dynamics Simulations of

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RESEARCH ARTICLE Advanced Science Letters

Copyright © 2014 American Scientific Publishers All rights reserved Printed in the United States of America

Vol. 20, 1637–1643, 2014

Docking and Molecular Dynamics Simulations of Pyrazolo[3,4-d]Pyrimidine-DNA Complexes Umesh Yadava1 ∗ , Hariom Gupta1 , Ramesh Kumar Yadav2 , and Mihir Roychoudhury1 1

Department of Physics, DDU Gorakhpur University, Gorakhpur 273009, India 2 Department of Physics, B.R.D.P.G. College, Deoria 274001, India

DNA molecule is a target for a number of anticancer and antiviral drugs that exhibits covalent and/or noncovalent interactions with major or minor grooves. The interaction studies of pyrazolo[3,4-d]pyrimidine compounds with purine rich DNA duplex 5 d(CAAAGAAAAG) ·5 d(CTTTTCTTTG) have been carried out through molecular docking and MD simulation methods. Glide Standard precision and Extra precision modules are used for docking. The docking energy, glide score and hydrogen bonding interactions as observed from both methods show that docking of pyrazolo[3,4-d]pyrimidine moieties connected with a trimethylene linker recognizes both the strands of DNA through hydrogen bonding interactions within the major groove of DNA. To study the stability of the docked complexes, Molecular Dynamics simulation of the best docked complex is carried out for 10.0 ns using DESMOND. RMSD calculations, energy variations and hydrogen bonding interactions indicate that the complex remain stable during the course of dynamics and Pyrazolo[3,4-d]pyrimidine compounds may be developed as the major groove binders.

Delivered by Publishing Technology to: Umesh Yadava IP: Pyrazolo[3,4-d]Pyrimidine, 129.98.43.172 On: Thu, 09 JulDocking, 2015 01:05:03 Keywords: DNA Duplex, Molecular Molecular Dynamics. Copyright: American Scientific Publishers

1. INTRODUCTION The DNA molecule is a target for a number of anticancer and antiviral drugs that exhibits covalent and/or noncovalent interactions with major or minor groove. Design, synthesis and binding studies of such compounds have been an area of immense interest among researchers for anti-cancer drug development.1–3 Interactions of these molecules with DNA can cause DNA damage in cancer cells, by inhibiting either replication or transcription and results in cell death or apoptosis.4 5 The most common right handed B-form DNA is biologically important because of its shallow wide major groove and deep minor groove and thus has been identified as an important target for cancer therapy. DNA acts as a noteworthy intracellular receptor and many molecules have been found to abide their antitumor activity by binding to it. DrugDNA interactions can be classified broadly into two categories namely, intercalators and groove binders. Both non-covalent and covalent bindings are possible in these types of classes. Intercalators are typically, planar aromatic molecules which bind between the layers of nucleic acid bases with less sequence specificity and disrupt the DNA organization.6 However, groove binders are small molecules that bind to DNA and play an important role in the development of drug. The capacity of groove binders is characterized by hydrogen bonding interactions, electrostatic environment, steric temperament and micro environmental polarity.7 Because of different dimensions, minor and major grooves ∗

Author to whom correspondence should be addressed.

Adv. Sci. Lett. Vol. 20, No. 7/8/9, 2014

requires immensely dissimilar and different shaped molecules. The major groove (∼11.6 Å), is much wider than the minor groove (∼6.0 Å). Due to this dimensional difference, the major grooves are also the site for binding of many DNA interacting peptides and proteins.7 However, small molecules were found to bind with both the major and minor groove regions of the doublehelical DNA with a slight preference toward the later mode of binding.8 The antitumor agent azinomycin-B forms the covalent interstrand cross-linking within the major groove via N7 alkylation of two purine bases9 which resulted in to several studies on it involving synthetic, mechanistic and molecular modeling studies.10 A number of compounds were synthesized and their interactions with DNA as minor and major groove binders were performed as the substitute for chemotherapeutic agents.11 12 The fused pyrimidines are an important class of compounds used as chemotherapeutic agents. Many therapeutic agents posses Pyrazole rings which have shown significant antiallergic, antiinflammatory and anti-arthritic properties.10 13 Many pyrazolopyrimidine containing fused heterocyclic compounds have exhibited biological activities, DNA binding affinities14 and widely studied in pesticide as well as medicine. Pyrazolo[3,4-d]pyrimidines constitute a class of naturally occurring fused uracils that exhibit various biological activities. These are reported as potential anti-inflammatory agents,15 anti-coagulation inhibitor,16 CNS depressant,17 tuberculostatic,18 xanthine oxidase inhibitor,19 antiproliferative and proapoptotic agents in several tumor types.20 They are also known as SRC kinase inhibitors21 and useful in

1936-6612/2014/20/1637/007

doi:10.1166/asl.2014.5590

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Adv. Sci. Lett. 20, 1637–1643, 2014

Delivered by Publishing Technology to: Umesh Yadava IP: 129.98.43.172 On: Thu, 09 Jul 2015 01:05:03 Copyright: American Scientific Publishers

Fig. 1. Chemical structure of ligands (pyrazolo[3,4-d]pyrimidine derivatives).

the treatment of human cancers sustaining oncogenic activation.22 Prompted by the various biological activities of pyrazolo[3,4d]pyrimidine derivatives (Fig. 1), we envisioned our approach towards the DNA binding potential of these molecules through in-silico docking studies with the duplex, 5 d(CAAAGAAAAG) · 5 d(CTTTTCTTTG).23 Molecular dynamics simulation of this A-tract DNA exhibit B-DNA conformation having malleable groove.24 The time evolution of the best docked poses, as obtained through docking, have been studies through molecular dynamics simulation.

2. METHODOLOGY 2.1. Molecular Docking The coordinate of DNA duplex 5 d(CAAAGAAAAG) · 5 d(CTTTTCTTTG) was retrieved from NDB entry (ID: BDJ081) (http://ndbserver.rutgers.edu/). The structure was carefully inspected and processed in order to overcome the potential problems like missing atoms, added water, bond orders etc. The crystal structure has three asymmetric units with similar conformations, one of which has been taken for the study. All the co-crystallized water molecules were removed and bond orders were reassigned. The duplex was prepared using protein preparation wizard of Schrodinger Suite25 where, hydrogens were added 1638

and the refinement of the structure was carried out. Coordinates of nine pyrazolo[3,4-d]pyrimidine ligand molecules (Fig. 1) were obtained from reported entries.26 27 Optimizations of these molecules have been performed through DFT B3LYP/6-31G** method using Gaussian03.28 Optimized coordinates of the ligands were prepared using the LIGPREP module where bond orders were modified according to their data. Different conformers of ligands were generated using CONFGEN each of which was subjected to a full minimization in the gas phase with the OPLS (Optimized Potential for liquid Simulations) force field29 to eliminate the bond length and bond angles biased from the crystal structure. Ligprep produced the structures with various ionization states, tautomers, stereo-chemistries, and ring conformations. The electron affinity and electrostatic potential grid for each type of atoms in ligands at different grid points, were calculated. Docking of the prepared duplex with prepared ligands have been carried out using Glide module in standard precision (SP) and extra precision (XP) modes respectively.25 Other parameters were same as reported in our earlier paper.16 After docking, post-docking minimization was also performed to improve the geometry of the poses which specifies a full force-field minimization of those poses which are considered for the final scoring. After minimization, the results were used for binding energy and docking scores calculations.

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2.2. Molecular Dynamics Simulation The better docked poses were selected from docking results and MD simulation was carried out on the best complex using DESMOND.30 Eighteen sodium counter ions were placed at appropriate distances to neutralize the system. The DNA and the counter ions were immersed in a Monte-Carlo-equilibrated, periodic TIP3P water bath. Water molecules and counter-ions were first energy minimized by steepest descent method and then by conjugate-gradient energy minimization. After the initial equilibration, molecular dynamics simulation was performed for 10.0 ns at 298 K temperature as in our earlier communication.24

3. RESULTS AND DISCUSSION 3.1. Glide-SP Docking Docking of pyrazolo[3,4-d]pyrimidine ligands with duplex revealed a great variation in their binding energy. The results

of Glide docking in Standard Precision mode are summarized in Table I. Initially, five poses of each molecule were saved from which the best pose with best G-score and lowest docking energy were chosen. Predicted free binding energy is a useful descriptor of ligand-receptor complementarities, hence the choice of the ‘best’ docking model was eventually dictated by different parameters of ADME study.16 These docked complexes were considered for further analysis. It has been observed that all the molecules recognizes both the strands of DNA through hydrogen bonding interactions. All the molecules bind within the major groove of the duplex. On the basis of glide score, molecule 6 can be placed at the first place while molecule 8, 7 and 3 receive the second, third and fourth place. Molecule 6 is asymmetrical class of molecule having one keto-methyl group and three thiomethyl groups whereas 7 has two thiomethyl groups but one pyrazolo[3,4-d]pyrimidine moiety is replaced by phthalimide moiety. Molecule 8 is similar to 7 but thiomethyl group

Table I. Glide scores (G_scores) and average vander Waal (Evdw), Coulomb (Ecoul) and Glide energies (G_energy) as obtained through Glide-SP docking. Entry id

G_score (kcal/mol)

Evdw (kcal/mol)

Ecoul (kcal/mol)

G_energy (kcal/mol)

1

24 36 38 39 40

−4024 −3847 −3845 −3834 −3827

−39855 −43920 −43588 −44235 −44237

−4388 −3913 −3613 −4132 −4071

−44233 −47833 −47201 −48367 −48308

2

27 33 49 111

−3977 −3890 −3753 Delivered−3196 by Publishing

−3678 −5297 −3079 −4751 Yadava

−41148 −41373 −40331 −42547

3

23 53 64 105 107

Molecules (SP)

−37470 −36077 −37258 −37796 to: Technology

Umesh IP: 129.98.43.172 On: Thu,−35595 09 Jul 2015 01:05:03 −4031 −3235 −3648 −36525 Publishers −3,433 Copyright: American Scientific −3596 −3279 −3261

−36287 −36808 −35394

−0460 −2986 −3057

−38631 −39958 −36747 −39794 −38451

4

57 58 66 68 76

−3628 −3627 −3579 −3570 −3496

−36212 −36255 −36087 −37886 −37417

−2861 −2815 −2889 −0678 −2849

−39073 −39070 −38977 −38563 −40266

5

25 26 31 32 37

−3991 −3983 −3907 −3896 −3846

−43167 −45880 −43617 −44092 −44316

−3752 −0203 −2994 −4636 −3183

−46919 −46084 −46611 −57728 −47499

6

2 4 5 6 7

−4638 −4574 −4572 −4567 −4565

−34993 −34618 −34582 −34669 −34559

−5798 −5803 −5819 −5764 −5818

−40791 −40421 −40401 −40433 −40378

7

10 11 14 15 17

−4428 −4404 −4308 −4305 −4246

−30121 −31141 −31229 −31439 −33690

−4380 −5569 −5735 −5524 −5045

−34502 −36710 −36964 −36963 −38735

8

3 8 9 12 22

−4584 −4513 −4435 −4399 −4036

−32873 −31008 −30781 −32477 −34636

−6384 −4873 −5004 −5571 −3331

−39257 −35881 −35785 −38048 −37967

9

45 51 52 54 55

−3785 −3659 −3654 −3648 −3648

−25141 −22776 −22709 −22706 −22707

−6352 −7900 −7937 −7931 −7930

−31492 −30776 −30645 −30637 −30637

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Table II. Hydrogen bonding interactions in the best docking complexes of molecules as obtained through Glide-SP docking. Entry

G-score (kcal/mol)

G_energy (kcal/mol)

Hydrogen-bonding

Distance (Å)

1

24

−4024

−44243

(DA4)N-H  C(LIG) (LIG)C-H  O(DG5) (LIG)C-H  N(DG5) (DA6)N-H..C(LIG) (LIG)C-H  O(DT13)

2489 2353 2290 2383 2396

2

27

−3977

−41148

(DA4)C-H  O(LIG) (LIG)C-H  O(DT15) (LIG)C-H  N(DA3)

2387 2385 2351

3

23

−4031

−38631

(LIG)C-H  O(DT15)

2353

4

57

−3628

−39073

(LIG)C-H  O(DG5)

2309

5

25

−3991

−46919

(LIG)C-H  N(DA3) (DA2)N-H  C(LIG) (DC16)N-H  C(LIG) (LIG)C-H  O(DT18)

2212 2431 2505 2392

6

2

−4638

−40791

(LIG) C-H  O(DG5) (DA6) N-H  C(LIG) (LIG) C-H  O(DT12)

2306 2477 2373

7

10

−4428

−34502

(LIG)C-H..N(DA3) (LIG)C-H  O(DC15)

2407 2350

8

3

−4584

−39257

(LIG)C-H  O(DG5) (LIG)C-H  O(DT14) (DA6)N-H  C(LIG)

2350 2338 2300

9

16

−4277

−29895

(LIG)C-H  O(DT14) (LIG)C-H  O(DT14)

2382 2399

Mol. (SP)

Table III. Glide scores (G_scores) and average vander Waal (Evdw), Coulomb (Ecoul) and Glide energies (G_energy) as obtained through Glide-XP docking. Mol. (XP) 1

Entry id 9 10 19 21 30

Docking score Evdw (kcal/mol) (kcal/mol) Delivered by(kcal/mol) Publishing Technology to: UmeshEcoul Yadava IP: 129.98.43.172 On: Thu,−39599 09 Jul 2015 01:05:03 −3076 −3157 −3057 −42370 Publishers −3921 Copyright: American Scientific

Glide energy (kcal/mol)

−2995 −2990 −2941

−41010 −39007 −40709

−4166 −2819 −3597

−42756 −46920 −45176 −41825 −44306

2

8 33 45 60

−3080 −2919 −2804 −2667

−36166 −33543 −36717 −33901

−1822 −4741 −3690 −4573

−37988 −38284 −40407 −38473

3

26 50 59 66 79 82

−2962 −2756 −2689 −2535 −2383 −2361

−33889 −32873 −31775 −29913 −31082 −33348

−2097 −3288 −1735 −3359 −3016 −0733

−35986 −40407 −33510 −33272 −34098 −34081

4

73 80 81 86 87

−2447 −2370 −2367 −2318 −2304

−36813 −33605 −33754 −33037 −32344

−1731 −1762 −2409 −1746 −0934

−38544 −35637 −36163 −34782 −33279

5

4 12 56 61 64

−3466 −3046 −2719 −2649 −2547

−43248 −40977 −34541 −37259 −43342

−2536 −3096 −2306 −2284 −2265

−45785 −44073 −36847 −39543 −45607

6

2 5 6 7 18

−3610 −3451 −3219 −3135 −3000

−34428 −34035 −33799 −36660 −32571

−4664 −3635 −5972 −3820 −6327

−38992 −37670 −39772 −40481 −38898

7

3 11 14 15 16

−3496 −3050 −3045 −3023 −3013

−28540 −31129 −29592 −30975 −29944

−3873 −5337 −4118 −5578 −4450

−32413 −36466 −33710 −36554 −34394

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Table III. Mol. (XP) 8

9

Continued. Entry id

Docking score (kcal/mol)

Evdw (kcal/mol)

Ecoul (kcal/mol)

Glide energy (kcal/mol)

13 22 28 42 43 53 65 69 71 72

−3045 −2988 −2961 −2835 −2816 −2737 −2545 −2494 −2480 −2467

−34592 −30766 −35709 −35374 −31968 −24906 −25819 −25195 −24880 −25467

−3928 −4640 −1466 −1212 −4689 −6364 −0858 −1451 −2208 −1298

−38520 −35406 −37175 −36585 −36657 −31270 −26677 −26646 −27088 −26764

at 4th position has been replaced by aliphatic pyrollidin moiety. Molecule 3 has two thiomethyl and two keto-methyl groups while 1 has tetra thioethyl substituents. It has also been observed that molecule 5 has the lowest glide energy (−46.919 kcal/mol) for the best docked pose which is a symmetrical class of molecule having bulky benzyl substituents. Symmetrical molecule 1 has the second lowest glide energy of −44.233 kcal/mol. Molecules 2, 3, 4, 6 and 8 are found to have almost similar energy values. Hydrogen bonding interactions as obtained through SP docking are depicted in Table II. Almost all the molecules have hydrogen bonding interactions. Maximum five number of hydrogen bonding interactions are exhibited by molecule 1. Molecule 5 shows four hydrogen bonding interactions while 2, 6 and 8 posses three hydrogen bonding interactions. Aromatic – interactions are also exhibited by all the molecules except molecule 9.

duplex and exhibit interactions within the major groove. XP module includes protein-ligand structural motifs leading to enhanced binding affinity, in addition to unique water desolvation energy terms. It can be observed from Table III that molecule 6 has the best docking score followed by molecules 7 and 5. Molecules 1, 2, 3 and 8 have similar scores, better than 4 and 9. For the best docked poses, molecule 5 has the best docking energy (−45.785 kcal/mol) while molecule 1 has the second best docking energy. Molecules 6, 4 and 8 posses slightly less magnitude but comparable energy values. XP docking further reveals that all molecules show hydrogen bonding interactions with both the strands of DNA. Molecules 2 and 8 have five, 4 has four while molecules 3, 5, 6 and 7 each have three number of hydrogen bonding interactions in the best docked poses as obtained through XP docking. Further, almost all the molecules show aromatic – interactions with DNA base pairs.

3.2. Glide-XP Docking Delivered by Publishing Technology to: Umesh YadavaSimulation 3.3. Molecular Dynamics Molecular docking of ligands with duplex through extra On: pre- Thu, IP: 129.98.43.172 09 Jul 2015 01:05:03 On the basis of glide score, glide energy and hydrogen bondcision module of Glide also reveal that all the American pyrazolo Scientific Copyright: Publishers ing interactions of the docking complexes, the DNA complexed [3,4-d]pyrimidine molecules recognize both the strand of DNA Table IV. Hydrogen bonding interactions in the best docking complexes of molecules as obtained through Glide-XP docking. Entry

G-score (kcal/mol)

G_energy (kcal/mol)

Hydrogen-bonding

Distance (H  A) (Å)

1 2

9 8

−3076 −3080

−42756 −37988

3

26

−2962

−35986

4

73

−2447

−38544

5

4

−3466

−45785

6

2

−3610

−38992

7

3

−3496

−32413

8

13

−3045

−38520

9

53

−2737

−31270

(DC16)N-H  N(LIG) (DA7)N-H  C(LIG) (DA6)N-H  O(LIG) (LIG)C-H  N(DG5) (DA4)N-H  C(LIG) (DA3)N-H  O(LIG) (DC16)N-H  N(LIG) (DA4)N-H  N(LIG) (DA6)N-H  O(LIG) (LIG)C-H  O(DT14) (LIG)C-H  C(DT15) (DC16)N-H  N(LIG) (DA4)N-H  N(LIG) (DA4)N-H  C(LIG) (DC16)N-H  N(LIG) (DA6)N-H  N(LIG) (DA6)N-H  O(LIG) (DC16)N-H  N(LIG) (DA4)N-H  N(LIG) (DA2)N-H..O(LIG) (DA3)N-H  N(LIG) (DA16)N-H  N(LIG) (DA3)N-H  O(LIG) (DA4)N-H  C(LIG) (DA4)C-H  N(LIG) (LIG)C-H  O(DT15) (LIG)C-H  N(DA6) (LIG)N-H  O(DA6) (DA7)N-H  N(LIG)

2111 2413 2259 2316 2442 2171 2291 2275 2244 2231 2594 2116 2334 2313 2067 2156 2037 2043 2195 2052 2089 2209 1974 2345 2354 2358 2446 1803 2122

Mol. (XP)

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Fig. 2.

Adv. Sci. Lett. 20, 1637–1643, 2014

Delivered by Publishing Technology to: Umesh Yadava IP: 129.98.43.172 On: Thu, 09 Jul 2015 01:05:03 Series of snap shots taken during MD simulation at the American interval of 1.0 Scientific ns. Copyright: Publishers

with molecule 6 has been chosen as the representative candidate for molecular dynamics simulation. After the initial equilibration, MD production run was carried out for 10.0 ns. A series of snap shots taken at the regular time interval of 1.0 ns are shown in Figure 2. Considering subtle changes in the torsion angle and helicoidal structure, the heavy-atom RMSDs indicate that the structure is considerably converged. Convergence

and stability profiles for the MD simulation are shown in Figure 3, in which the RMSDs of MD structure as a function of time have been plotted for all heavy atoms. The results indicate that the MD structure transits quickly in the simulation to 6.5 Å RMSD from the initial structure, with reasonably small oscillations. The range of oscillation of the dynamical structure around the MD average is ±0.5 Å. The variation of total energy of the complex is found to be centered about −70 kcal/mol. It has been observed that the main contribution in the total energy comes out from the electrostatic energy, while vander Waal energy is more negative than the electrostatic energy which indicates about the good pose of ligand to acquire the cavity of receptor. RMSD calculations, energy variations and hydrogen bonding interactions indicate that the complex remains stable during the course of dynamics and Pyrazolo[3,4d]pyrimidine compounds may be developed as the major groove binders.

4. CONCLUSION

Fig. 3. RMSD deviation of average MD simulated structure as a function of time.

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The malleable groove width makes DNA capable to bind with any molecule which satisfies the favorable environmental conditions. Molecular docking through both methods (SP and XP) show that pyrazolo[3,4-d]pyrimidine moieties connected with a trimethylene linker, recognizes both the strands of DNA duplex through hydrogen bonding and – interactions within the major groove. MD simulation study shows that the complex

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Adv. Sci. Lett. 20, 1637–1643, 2014

remain stable during the course of dynamics. These results indicate that pyrazolo[3,4-d]pyrimidine compounds may be developed as the major groove binders.

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References and Notes

IP: 129.98.43.172 On: Thu, 09 Jul 2015 01:05:03 Copyright: American Scientific Publishers Received: 12 June 2014. Accepted: 10 July 2014.

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