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

Brijesh      Patel; Saurabh   M.   Verma; Kalyan   K.   Sethi

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.

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