3D-QSAR and Docking studies of N-hydroxy 1,8-naphthyridine 2-one analogues as Ribonuclease H Inhibitors

Abstract

Three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed for a series of ribonuclease H inhibitors using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and docking studies. A large set of 33 different aromatic/ heterocyclic N-hydroxy 1,8- naphthyridine 2-one analogs as Ribonuclease H inhibitors wher chosen for the present study. The naphthyridine ring of the n-hydroxy 1,8-naphthyridine 2-one gives the class of compounds which has the ability to chelate metal cations Mn2+ present in RNase H active. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q2 values 0.663 and 0.512 and r2 values 0.997 and 0.999 for CoMFA and CoMSIA respectively and the predictive ability of the model was also evaluated. The predicted r2 values were 0.660 and 0.650 for CoMFA and CoMSIA, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. N-hydroxy 1,8-naphthyridine 2-one binds an RNA:DNA substrate, the RT/RNA:DNA structure (PDB code: 1HYS) was superimposed on our RT/N-Hydroxy 1,8-Naphthyridine 2-one (3QLH) structure (residues Val442 to Asp443, Glu478, and Asp549). Present study indicates that the CoMFA and CoMSIA models along with molecular docking could be reliable to establish a suitable molecular model which may be used in the design of novel ribonuclease H inhibitors as leads. Keywords: N-hydroxy 1, 8-naphthyridine 2-one, Ribonuclease H inhibitors, 1HYS, Docking, CoMFA, CoMSIA.