Skip to main content

Insilico design, ADMET screening, MM-GBSA binding free energy of novel 1,3,4 oxadiazoles linked Schiff bases as PARP-1 inhibitors targeting breast cancer



Poly(ADP-ribose) polymerases (PARPs), a nuclear protein belongs to a new class of drugs, which mainly target tumours with DNA repair defects. They are mainly involved in the multiple cellular processes in addition to the DNA repair process. They act directly on the base excision repair, which is considered as one of the important pathway for cell survival in breast cancer. These belong to the active members of DNA repair assembly and evolved as a key target in the anti-cancer drug discovery. 1,3,4-Oxadiazoles are also well known anticancer agents.


A novel series of 1,3,4-oxadiazoles linked to Schiff bases (T1-21) were designed and subjected to In-silico analysis against PARP-1 (PDB ID:5DS3) enzyme targeting against breast cancer. Molecular docking study for the designed compounds (T1-21) was performed by In-silico ADMET screening by QikProp module, Glide module and MM-GBSA binding free energy calculations by using Schrodinger suit 2019–2. The PARP-1 enzyme shows the binding affinity against the newly designed molecules (T1-21) based on the glide scores. Compounds T21, T12 showed very good glide score by the molecular docking studies and compared with the standard Tamoxifen. The binding free energies by the MM-GBSA assay were found to be consistent. The pharmacokinetic (ADMET) parameters of all the newly designed compounds were found to be in the acceptable range.


The selected 1,3,4-oxadiazole-schiff base conjugates seems to be one of the potential source for the further development of anticancer agents against PARP-1 enzyme. The results revealed that some of the compounds T21, T17, T14, T13, T12, T8 with good glide scores showed very significant activity against breast cancer


Cancer is a large group of diseases. According to WHO, cancer causes the second highest mortality rate after the cardiac disease in humans [1]. The number of new cases of cancer escalated to 19.3 million and caused 10.0 million deaths in the year 2020 Males are primarily affected by cancers of liver, prostrate, lung, stomach, colon and rectum while females are primarily affected by breast, cervix, colorectal, lung, and thyroid cancer. Treatment of cancer treatment has spawned an entirely new field of research involving both conventional and modern technologies. The global surge in the spread of cancer has led to 70% of the cancer mortality rate all over the world [2].

Breast cancer constitutes one of the most frequently occurring cancer in females around the world, with 3,50,000 deaths each year. Chemotherapy can be used to treat many malignant tumours, so looking for new chemotherapeutic drugs is still important [3]. The fact that, one out of every five women is diagnosed with breast cancer, necessitates the development of new compounds to treat the disease [4]. Over the years, scientists have collaborated with specific remedial experts to develop a target for bosom malignant growths. Human Epidermal development factor Receptor-2 (HER2) [5,6,7], Estrogen Receptor (ER) [8, 9], & vascular endothelial development factor (VEGF) [10, 11] are some of the targets for breast malignant growth. Epidermal Growth Factor Receptor (EGFR) [12, 13], Poly ADP ribose polymerase (PARP) [14,15,16], BRCA1 (Breast disease type 1 helplessness protein) [17, 18], TKI (tyrosine kinase inhibitor) [19, 20], CDK4/6 (cyclin subordinate kinase) inhibitors [21] etc. and so on.

The PARP-1 enzyme has recently gained a great deal of attention as a potential anti-cancer agent because it belongs to the PARP family of proteins that are essential to the single-stranded DNA repair process [22]. These are the group of enzymes and a type of targeted therapy, which plays a key role in transcriptional regulation, cell death and DNA repair. Since they are involved in the DNA repair they are called as guardian angel of DNA. PARP-1 also plays a crucial role in a variety of cell-based processes, including cell differentiation and cell division. PARP-1 inhibitors inhibit mitosis, inflammation, gene transcription, and finally cause cell death, all of which result in cytotoxic potential. PARP-1 inhibitions are based on the existence of BRC A 1/2 mutations, which are essential protein for DNA, breaks in homologous recombination (HR) double-stranded breaks [23], since the mutated cancer cells use PARP-1 in order to remedy and cellular survival [24, 25]. As a result, PARP-1 inhibitors have the potential to cause cell death selectively, especially in breast and ovarian cancers [26]. The FDA has already licenced many PARP-1 inhibitors, including BMN673 (Talazoparib), AZD2281 (Olaparib), AG014699 (Rucaparib), MK4827 (Niraparib) [27,28,29]. It is found that PARP-1 easily catalyses the required division of NAD + (nicotinamide adenine dinucleotide) into ADP and nicotinamide ribose units. In response to DNA damage [30], these are transferred to various acceptor proteins involved in the DNA damage repair process such as ADP-ribose polymers (PAR) and histones. The enzyme PARP-1 is basically composed of two active binding sites, namely adenine-ribose binding site (AD site) and nicotinamide-ribose (NI site) [31].

The proposed PARP inhibitors (1,3,4-oxadiazole derivatives), in the presence of DNA damage, the PARP inhibitors prohibit PARylation from occurring and these PARP-1 will remains very tightly bound to the damaged sites [32]. The later action, is due to the binding affinity of PARP-1 to the damaged DNA is very much increased and this process is called as PARP trapping [33]. The cell death is due to the homologous recombination deficiency (HRD) and the synthetic lethality mediated by the PARP inhibition. Some of the previous studies very efficiently demonstrated, the cells which are deficient in BRCA1 or BRCA2, will display an increased sensitivity towards the PARP inhibitors at least by about 1000 fold times [34]. Based on the above observations, the PARP inhibition is found to be a one of the promising therapeutic strategy for homologous recombination-deficient tumours, which are mainly associated with BRCA mutations. Thus the use of PARP inhibitors can potentially be expanded to tumours without BRCA mutations [35].

1,3,4-Oxadiazoles are found to be an one of the important class of heterocyclic compounds with very large diversified activities and good bio-isosteres of amide and ester, participate with the receptor through hydrogen bonding and increase the biological profile to a large extent [36]. Five membered 1,3,4-oxadizole analogues are rich in potential activities [37]. The central ring of the 1,3,4-oxadiazole moiety contains toxophoric –N=C–O– linkage [38] and considered as one of the important group, which might be responsible for their potent pharmacological activities including anticancer activity. In the recent time lot of interest is created over the synthesis of these compounds due to their higher antitumor activity [39]. Similarly, the Schiff bases are also reported for various pharmacological actions due to its >C=N group, and found to possess the antitumor activity [40]. Based on the above facts, the present work was designed to report a new series of 1,3,4-oxadiazole derivatives clubbed with Schiff bases containing the active C=N group at its second position.

The present work is aimed at targeting PARP-1 enzyme against breast cancer, by the new class of hybrids of 1,3,4-oxadiazoles and Schiff bases by the In-silico approach.


In silico studies

Protein preparation

The protein data bank yielded PARP-1 inhibitors with co-crystalline ligand (PDB ID: 5DS3 2.3A0). The protein was established using the Schrodinger suite 2019–2 protein preparation wizard module. Water atoms which are more than 5 A0 and do not have hydrogen bonds are evacuated. The primary module of the Schrodinger suite 2019–2 is used to fill missing chain iotas. For the heteroatoms in the protein, all possible ionisation states were formed, and the state with the highest degree of stability was chosen. Following that, the OPLS3 force field was used to conduct a controlled energy minimization of the protein structure in order to reorient the side-chain hydroxyl groups and reduce the probability of steric clashes [41].

Receptor grid set to generation

The co-crystallized ligand was housed in the crystal structure of the protein, which was developed using the protein preparation wizard. To describe the centroid of the dynamic site used for docking, a Gride box (14Ao × 14Ao × 14Ao) was generated using the Glide grid generation wizard [41].

Ligand preparation

The required ligands T1-21is showed in Fig. 1 and docked onto the pocket of PARP-1 protein. (PDB ID: 5DS3). Chemsketch software was used to build the ligand structures, which were then subjected to the LigPrep module of the Schrodinger suite 2019. Ligands were converted to 3D structures through stereo concoction, ionisation, and tautomerism, as well as vitality minimization and geometry optimization, and they were also dissolved and rectified for the absence of hydrogen atoms and chiralities. Finally, the mixes were limited using the optimized potentials for liquid simulations-3 (OPLS-3) power field in the Schrodinger Impact package until a root mean square deviation of 1.8Ao was achieved. A single low-energy ring confirmation was made for each ligand, and the streamlined ligands were used for docking studies.

Fig. 1
figure 1

Structures of designed compounds (T1-21)

Glide ligand docking

The ligands are located in the synergist pocket of the PARP-1 protein with the Schrodinger suite 2019–2's Glide module (PDB ID: 5DS3). The Glide score is used to select the ligands that are best covered. The Glide ligand docking module was used to test active relationships between ligands and receptors. Docking was done in a versatile docking mode that automatically generates conformations for each input ligand, using extra precision (XP) mode and the OPLS-3 power field. Positive interactions such as lipophilia, hydrogen bonding, and metal-linking are rewarded, while steric conflicts are punished. Finally, re-scoring of a few positions was done via glide score's ability to score. The docking results were analysed using the Glide module's XP visualizer. The Glide score of the standard compounds containing Olaparib & compounds with hostile to bosom malignancy tranquillize, tamoxifen was condensed and contrasted. Glide score capability is primarily determined by docking parameters, such as lipophilic perseverance, wherein the compounds are secured in the lipophilic pocket, which is important for action control. The Schrodinger suit-2019 QikProp module was used to detect the ligands' ADMET properties [41].

Calculation of bind free energy using MM-GBSA

MM-GBSA assay helps to know the binding free energy of protein–ligand complexes. The Schrodinger suite 2019–2 Prime module (the OPLS3 power field and the dissolvable model VSGB) is used to process the drug-receptor complex's binding free energy using the MM-GBSA assay process [42].


The affinity of the compounds (T1-T21) with receptor PARP-1 (PDB ID: 5DS3) is given Table 1 in terms of Glide scores. The docking studies were carried out in order to know the binding mode of all the designed analogues into the active site of PARP-1 at atomic levels. The compounds Glide docking score were in the range from − 6.357 to − 3.723 kcal/mol. Trp 861, His 862, Gly 863, Ser 864, Arg 865, Asn 868, Gly 876, Leu 877, Arg 878, Phe 891, Ile 895, Tyr 896, Phe 897, Ala 898, Lys 903, Ser 904, Tyr 907, Asn 987, Glu 988, Tyr 989 are the active residues in 5DS3. Compound T21 has the highest Gscore of 6.357 kcal/mol, followed by compound T12 with a G score of 5.938 kcal/mol. represents the structures of the designed compounds and Figs. 2, 3, 4 and 5 represents the 2D docking of these compounds with PDB ID: 5DS3, respectively. These compounds demonstrate pi-pi stacking with Tyr 907. Compound T21 forms hydrogen bonds with Phe 897, Gly 863 and Ser 904. Compound T12 forms hydrogen bonds with Met 890 and Ser 904. Some of the other designed compounds T8, T10, T13, T17 also showed very good G scores when compared to the standard drugs.

Table 1 Docking studies for compounds (T1-21) with PARP-1 (5DS3)
Fig. 2
figure 2

Ligand interaction of compound T12 and T13 with PARP-1 5DS3

Fig. 3
figure 3

Ligand interaction of compound T17 and T21 with PARP-1 5DS3

Fig. 4
figure 4

Ligand interaction of compound T8 and T14 with PARP-1 5DS3

Fig. 5
figure 5

Ligand interaction of Standard Tamoxifen and Olaparib with PARP-1 5DS3

The ADMET properties of all the designed compounds are predicted by qikprop module of Schrödinger suite 2019.2 Table 2. The molecular weight of all the compounds found below 500 and also the dipole moments showed zero. All the compounds obeyed Lipinski’s rule of five as the molecular weight, the number of hydrogen bond donors and acceptors, and Log P values were all within the acceptable limits. Qikprop also helps to know #metab, the number of probable metabolic reactions. It aids to predict the ease with which the drug might approach the target. All the designed compounds lie within the recommended range of 1–8. Owing to the fact that the % human oral absorption of all the compounds were > 80%, there would be no effect on the bioavailability of the compounds, in case of deviation from the Lipinski’s rule of five. Among the designed compounds T10, T17 and so many others also displayed 100% human oral absorption.

Table 2 Insilico ADMET screening for proposed compounds (T1-21)

MM-GBSA assay

The target protein and the respective protein were prepared as per the depicted structure Fig. 1. All the proposed analogues, showed good free binding energy, which will fit well into the PARP-1 receptor Table 3. The binding free energies of the Compound T17 has the highest ΔG binding energy to 5DS3 with a value of -73.9 kcal/mol when compared to the known standard drug, Tamoxifen having a ΔG binding energy of − 65.62 kcal/mol.

Table 3 Binding free energy calculation using Prime/MM-GBSA approach of compounds (T1-T21)


Molecular docking studies assessments were performed to understand the interactions of compound (T1-T21) (Fig. 1, Table 1) with Poly [ADP-ribose] polymerase-1(PARP-1). The binding modes of the designed compounds were investigated by using Molecular docking tools [42]. The coordinates and structure factors for the reported X-ray crystal structures have been deposited in the PDB: ID: 5DS3, the latter is responsible for PARP-1 inhibitory activity [43]. The docking studies of the newly designed compounds involve several molecular interactions, in order to bind into the active site of target. These interactions will be responsible for the profound affinity to these compounds. The glide scores which are obtained from the docking studies against PDB: 5DS3 were showed in Table 1 and the results were compared with standard Olaparib and Tamoxifen. The binding affinity is due to the lipophilic factors and it is due to the presence of five membered heterocyclic ring and 1,3,4-oxadiazole moiety.

In accordance to the Lipinski’s RO5, the molecular weight of the molecule should be ≤ 500, partition coefficient ≤ 5, the number of hydrogen bond donors and acceptors should be ≤ 5 and ≤ 10, respectively. All these properties along with molecular flexibility are regarded as essential determinants of oral bioavailability. Hence, the compounds ability to obey this rule was evaluated and all the designed compounds obey’s Lipinski’s RO5. The results from the In-silico ADMET screening, most of the designed compounds are within the recommended values. The results are shown in Table 2.

Prime MM-GSBA analysis (Table 3) depicts the relative energies of binding of each compound with that of the receptor. It is a culmination of numerous drug-receptor interactions including polar interaction, hydrophobic interaction, covalent bond interactions etc. The results of MM-GBSA assay showcase that the energies which strongly ligand binding in the binding pocket of 5DS3 are Van der Waals energy (ΔGvdW) and non-polar solvation (ΔGLipo) owing to the high negative values displayed by all the compounds. The other energies, namely covalent energy (ΔGCov) and electrostatic solvation (ΔGSolv) energy do not strongly favour receptor binding. Further, the higher values of ΔGVdW and ΔGLipo in the negative range show remarkable hydrophobic interaction with 5DS3 and ligands T1-21. Highly favoured ligand binding was observed in compounds T7, T10, T13, T14 and T21. This result can be correlated to the G score as well since compound T21 displayed highest docking score implying that columb energy (ΔGCoul- 39.94 to -18.95 kcal mol-1). plays a vital role in the drug-receptor interaction. It can be observed through the MM-GSBA assay, that strong binding affinities of the compounds T5, T8, T18, T20 and the receptor are visible.


1,3,4-oxadiazoles have gained a lot of medicinal importance due to their varied pharmacological and biological profile, thereby making an unique molecule for various studies. Similarly, Schiff bases are well known compounds in the organic chemistry field. The hybrids of these moieties, was explored for possible anticancerous activity by In-silico studies. The study reveals, the presence of Schiff bases, which is linked to the 1,3,4-oxadiazole moiety, showed very good binding energy and G score. The selection of PARP-1 enzyme has showed promising activity by these hybrid molecules. However still it requires further In-vitro and In-vivo studies to confirm their further SAR. The In-silico studies, have greatly exhibited anticancer property, in the designed molecules. The compounds T21, T17, T14, T13, T12, T8 showed a significant antibreast cancer activity and these analogues are found to be one of the promising molecules and requires further modifications in the structural requirement.

Availability of data and materials

All data and materials are available upon request



Poly ADP ribose polymerase


Absorption, distribution, metabolism, excretion, and toxicity


Structural activity relationship


Molecular mechanics/Generalized born surface area 3D Qsar


Protein data bank


Extra precision


Molecular weight

Δ G bind:

Free energy of binding


Breast cancer gene


  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of Incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249.

    Article  PubMed  Google Scholar 

  2. Tyczynski JE, Plesko I, Aareleid T, Primic-Zakelj M, Dalmas M, Kurtinaitis J, Stengrevics A, Parkin DM (2004) Breast cancer mortality patterns and time trends in 10 new EU member states: mortality declining in young women, but still increasing in the elderly. Int J Cancer 112(6):1056–1064.

    CAS  Article  PubMed  Google Scholar 

  3. Kalirajan R, Pandiselvi A, Gowramma B, Balachandran P (2019) In-silico design, ADMET screening, MM-GBSA binding free energy of some novel isoxazole substituted 9-anilinoacridines as HER2 inhibitors targeting breast cancer. Curr Drug Res Rev Formerly Current Drug Abuse Rev 11(2):118–128.

    CAS  Article  Google Scholar 

  4. Baselga J, Tripathy D, Mendelsohn J et al (1996) Phase II study of weekly intravenous recombinant humanized anti-p185her2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14(3):737–744.

    CAS  Article  PubMed  Google Scholar 

  5. Baselga J, Cleopatra SSM (2010) A phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 10(6):489–491.

    Article  PubMed  Google Scholar 

  6. Burris HA III, Rugo HS, Vukelja SJ et al (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of H Human epidermal growth factor R Receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29(4):398–405.

    CAS  Article  PubMed  Google Scholar 

  7. Chang BY, Kim SA, Malla B, Kim SY (2011) The Effect of Selective Estrogen Receptor Modulators (SERMS) on the Tamoxifen resistant breast cancer cells. Toxicol Res 27(2):85–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D (1998) Regulation of macrophage production of Vascular Endothelial Growth Factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol 5(3):271–278.

    CAS  Article  PubMed  Google Scholar 

  9. Lai L, Liu J, Zhai D et al (2012) Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor-2. Br J Pharmacol 165(4b):1084–1096.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Miller KD, Trigo JM, Wheeler C et al (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11(9):3369–3376.

    CAS  Article  PubMed  Google Scholar 

  11. Perez EA, Romond EH, Suman VJ et al (2011) Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 29(25):3366–3373.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Sasaki T, Hiroki K, Yamashita Y (2013) The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Bio-Med Res Int.

    Article  Google Scholar 

  13. Langelier MF, Ruhl DD, Planck JL, Kraus WL, Pascal JM (2010) The Zn3 domain of human poly (ADP-ribose) polymerase-1 (PARP-1) functions in both DNA-dependent poly(ADP-ribose) synthesis activity and chromatin compaction. J Biol Chem 285(24):18877–18887.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Lord CJ, Ashworth A (2008) Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 8(4):363–369.

    CAS  Article  PubMed  Google Scholar 

  15. Yuan Z, Chen S, Chen C, Chen J, Chen C, Chunmei DQ, Gao YJ (2017) Design, synthesis and biological evaluation of 4-amidobenzimidazoleacridine derivatives as dual PARP and Topoinhibitors for cancer therapy. Eur J Med Chem 138:1135–1146.

    CAS  Article  PubMed  Google Scholar 

  16. Lee JM, Hays JL, Annunziata CM et al (2014) Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 106(6):dju089.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Qin T, Huang G, Chi L et al (2017) Exceptionally high UBE2C expression is a unique phenomenon in basal-like type breast cancer and is regulated by BRCA1. Biomed Pharmacother 95:649–655.

    CAS  Article  PubMed  Google Scholar 

  18. Ocaña A, Amir E (2009) Irreversible pan-erbb tyrosine kinase inhibitors and breast cancer: Current status and future directions. Cancer Treat Rev 35(8):685–691.

    CAS  Article  PubMed  Google Scholar 

  19. Arora A, Scholar EM (2005) Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 315(3):971–979.

    CAS  Article  PubMed  Google Scholar 

  20. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL (1997) Estrogen-induced activation of CDK4 and CDK2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 272(16):10882–10894.

    CAS  Article  PubMed  Google Scholar 

  21. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10(4):293–301.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Page P, Li-Xi Y (2010) Novel chemo radiosensitizers for cancer therapy. Anticancer Res 30:3675–3682

    CAS  PubMed  Google Scholar 

  23. Bock FJ, Chang P (2016) New directions in poly(ADP-ribose) polymerase biology. The FEBS J 83:4017–4031.

    CAS  Article  Google Scholar 

  24. Bryant HE, Schultz N, Thomas HD, Parker KM et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917.

    CAS  Article  PubMed  Google Scholar 

  25. Yap TA, Sandhu SK, Carden CP, De Bono JS (2011) Poly (ADP-Ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin 61(1):31–49.

    Article  PubMed  Google Scholar 

  26. Scully R, Puget N (2002) BRCA1 and BRCA2 in hereditary breast cancer. Biochimie 84(1):95–102.

    CAS  Article  PubMed  Google Scholar 

  27. Curtin N (2014) PARP inhibitors for anticancer therapy. Biochem Soc Trans 42:82–88.

    CAS  Article  PubMed  Google Scholar 

  28. Nonomiya Y, Noguchi K, Katayama K, Sugimoto Y (2019) Novel pharmacological effects of poly (ADP-ribose) polymerase inhibitor rucaparib on the lactate dehydrogenase pathway. Biochem Biophys Res Comm 510(4):501–507.

    CAS  Article  PubMed  Google Scholar 

  29. Sahu B, Narota A, Naura AS (2020) Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib, prevents acute lung injury associated cognitive deficits potentially through suppression of inflammatory response. Eur J Pharmacol 877:173091.

    CAS  Article  PubMed  Google Scholar 

  30. Lehtiö L, Jemth AS, Collins R, Loseva O et al (2009) Structural basis for inhibitor specificity in human poly (ADP-ribose) polymerase-3. J Med Chem 52:3108–3111.

    CAS  Article  PubMed  Google Scholar 

  31. Ramadan SK, Elrazaz EZ, Abouzid KA, El-Naggar AM (2020) Design, synthesis and in silico studies of new quinazolinone derivatives as antitumor PARP-1 inhibitors. RSC Adv 10(49):29475–29492

    CAS  Article  Google Scholar 

  32. Murai J, Shar-yin NH, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Can Res 72(21):5588–5599.

    CAS  Article  Google Scholar 

  33. Pommier Y, O’Connor MJ, de Bono J (2016) Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 8:362ps17.

    CAS  Article  PubMed  Google Scholar 

  34. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921.

    CAS  Article  PubMed  Google Scholar 

  35. Keung MY, Wu Y, Vadgama JV (2019) PARP inhibitors as a therapeutic agent for homologous recombination deficiency in breast cancers. J Clin Med 8(4):435.

    CAS  Article  PubMed Central  Google Scholar 

  36. Zhang K, Wang P, Xuan LN, Fu XY, Jing F, Li S, Liu YM, Chen BQ (2014) Synthesis and antitumor activities of novel hybrid molecules containing 1, 3, 4-oxadiazole and 1, 3, 4-thiadiazole bearing Schiff base moiety. Bioorganic Med Chem Lett 24(22):5154–5166.

    CAS  Article  Google Scholar 

  37. Vaidya A, Jain S, Jain P, Jain P, Tiwari N, Jain R et al (2016) Synthesis and biological activities of oxadiazole derivatives: a review. Mini Rev Med Chem 16(10):825–845.

    CAS  Article  PubMed  Google Scholar 

  38. Zarghi A, Hamedi S, Tootooni F, Amini B, Sharifi B, Faizi M, Abbas S, Abbas ST (2008) Synthesis and pharmacological evaluation of new 2-substituted-5-{2-[(2 halobenzyl)thio)phenyl}- 1,3,4-oxadiazoles as anticonvulsant agents. Sci Pharm 76(2):185–201.

    CAS  Article  Google Scholar 

  39. Aboraia AS, Abdel-Rahman HM, Mahfouz NM, EL-Gendy MA (2006) Novel 5-(2-hydroxyphenyl)-3-substituted-2, 3-dihydro-1, 3, 4-oxadiazole-2-thione derivatives: Promising anticancer agents. Bio-org Med Chem 14(4):1236–1246.

    CAS  Article  Google Scholar 

  40. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27(3):221–234.

    CAS  Article  PubMed  Google Scholar 

  41. Gálvez J, Polo S, Insuasty B, Gutiérrez M, Cáceres D, Alzate-Morales JH, De-la-Torre P, Quiroga J (2018) Design, facile synthesis, and evaluation of novel spiro-and pyrazolo [1, 5-c] quinazolines as cholinesterase inhibitors: Molecular docking and MM/GBSA studies. Comput Biol Chem 74:218–229.

    CAS  Article  PubMed  Google Scholar 

  42. Hassan AS, Askar AA, Nossier ES, Naglah AM, Moustafa GO, Al-Omar MA (2019) Antibacterial evaluation, in silico characters and molecular docking of Schiff Bases derived from 5-aminopyrazoles. Molecules 24(17):3130.

    CAS  Article  PubMed Central  Google Scholar 

  43. Dawicki-McKenna JM, Langelier MF et al (2015) PARP-1 activation requires local unfolding of an 013autoinhibitory domain. Mol Cell 60(5):755–768.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


The author express sincere thanks to NGSM Institute of Pharmaceutical Science and Nitte (Deemed to be University) Mangalore, Karnataka and NGSM-CADD Lab for providing all the necessary facilities required to carry out this research work.


Not applicable.

Author information

Authors and Affiliations



BCR did the conception of work, design of the work, experimental work and the interpretation of data and drafting of the manuscript. GSM, SD contributed in the design of work, experimental work done, results analysis. NNA, BFDG helped in carrying out the designed work, interpretation of data and critical revision of the manuscript. BCR reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bistuvalli Chandrashekharappa Revanasiddappa.

Ethics declarations

Ethics approval and consent of participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shridhar Deshpande, N., Mahendra, G.S., Aggarwal, N.N. et al. Insilico design, ADMET screening, MM-GBSA binding free energy of novel 1,3,4 oxadiazoles linked Schiff bases as PARP-1 inhibitors targeting breast cancer. Futur J Pharm Sci 7, 174 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Cancer
  • PARP-1
  • Breast cancer
  • 1,3,4 oxadiazoles
  • In-silico ADMET screening
  • MM-GBSA assay