Currently dengue is a serious disease which has become a global burden in the last decade. Unfortunately, there are no effective drugs and vaccines against this disease. DENV non-structural protein (NS) 3, which is viral protease which is a potential target for antiviral therapy. Targeting this we performed homology modeling and protein-protein docking study of NS3 with NRBP (Nuclear Receptor Binding Protein) of human as it has been proved that NS3 of DENV interacts with NRBP which causes cellular trafficking in human cell. To carry out search of novel DENV protease inhibitors by in silico screening panduratin molecule was selected. 65 novel compounds were designed which involved substituting positions 1-5 of the benzyl ring A (4hydroxy-panduratinA) with various substituents. The protein-protein docking showed that the aminoacid residues of NS3 which were interacting with NRBP were found to be Ala 325, Asp 324, Phe 326, Asp 335, Glu 336, Glu 328, Asp 485, Gln 478, Arg 459, Gly 446 and Leu 480. These residues were targeted by the ligands which showed excellent binding affinity as binding energy. The ligand PKP10 showed lowest binding energy. It is also observed that the interface residues participated in the protein-protein interaction are being inhibited by the ligands.