Abstract
BackgroundPoly(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.ResultsA 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.ConclusionThe 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
Highlights
Poly(ADP-ribose) polymerases (PARPs), a nuclear protein belongs to a new class of drugs, which mainly target tumours with DNA repair defects
Chemotherapy can be used to Shridhar Deshpande et al Futur J Pharm Sci (2021) 7:174 treat many malignant tumours, so looking for new chemotherapeutic drugs is still important [3]
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
Summary
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. 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
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