Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches

Abstract

. (2015). Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches. Journal of Molecular Graphics and Modelling, 57 1-8. Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches AbstractThe nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structurebased approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations. The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The results provide valuable information for the development of inhibitors for CHIKV. AbstractThe nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structure-based approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations.The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The resu...

Design and Validation of Novel Chikungunya Virus Protease Inhibitors

“…Similarly, several potential inhibitors were identified using a combination of molecular docking, virtual screening, and molecular dynamics simulations on the crystal structure of CHIKV nsP2 protease (31). The best compounds were characterized by binding free energies up toϪ10.6 kcal/mol.…”

Advances in structure-assisted antiviral discovery for animal viral diseases

“…To find out a few potential inhibitors against CHIKV nsp2 protease, homology modeling and computer-aided drug design strategies have been implemented for the first time (Bassetto et al, 2013). Potential inhibitors based on structural studies and molecular simulations have been reported (Nguyen et al, 2015;Singh et al, 2012).…”

Skrining Turunan Flavonoid Sebagai Kandidat Inhibitor Protease nsP2 dari Virus Chikungunya Menggunakan Molecular Docking

“…Penelitian tentang pencarian sisi aktif protease nsP2 dari virus chikungunya telah banyak dilakukan. Pocket 4 pada N-terminal protease nsP2 diidentifikasi sebagai sisi aktif yang potensial untuk dijadikan target inhibisi oleh suatu inhibitor dengan adanya residu katalitik Cys1013 dan His1083 (Nguyen, et al, 2015). Residu-residu asam amino Cys1013, Trp1014, Ala1046, Tyr1047, Ser1048, Tyr1084, Asn1082, Leu1205, Gly1206, Mse1238, Gln1241, Mse1242, dan Asp1246 menunjukkan interaksi yang krusial dengan protease nsP2 (Agarwal, et al, 2015).…”

“…Hasil visualisasi dengan software Edu PyMOL, ligan kelompok flavonoid yang digunakan berada dalam satu sisi pengikatan yang sama dengan ligan kontrol pada penelitian Nguyen, et al tahun 2015. Ligan kontrol berada pada pocket 4 yang berisi residu-residu asam amino, yaitu Cys1013, Ala1046, Tyr1047, Ser1048, Pro1049, Glu1050, Val1051, Tyr1078, Tyr1079, Asn1082, His1083, Trp1084, Gly1090, Lys1091, Phe1093, Tyr1201, Asn1202, Glu1204, Leu1205, Gly1206, Pro1208, Ala1209, Met1238, Gln1241, Met1242, Gly1245, Asp1246 dan Arg1249 (Nguyen, et al, 2015). Berikut ini merupakan data residu asam amino yang berikatan langsung dengan ligan golongan flavonoid yang disajikan pada Tabel 4.…”