Discovering key residues of dengue virus NS2b-NS3-protease: New binding sites for antiviral inhibitors design.
The NS2B-NS3 protease is essential for the Dengue Virus (DENV) replication process. This complex constitutes a target for efficient antiviral discovery because a drug could inhibit the viral polyprotein processing. Furthermore, since the protease is highly conserved between the four Dengue virus serotypes, it is probable that a drug would be equally effective against all of them. In this article, a strategy is reported that allowed us to identify influential residues on the function of the Dengue NS2b-NS3 Protease. Moreover, this is a strategy that could be applied to virtually any protein for the search of alternative influential residues, and for non-competitive inhibitor development. First, we incorporated several features derived from computational alanine scanning mutagenesis, sequence, structure conservation, and other structure-based characteristics. Second, these features were used as variables to obtain a multilayer perceptron model to identify defined groups (clusters) of key residues as possible candidate pockets for binding sites of new leads on the DENV protease. The identified residues included: i) amino acids close to the beta sheet-loop-beta sheet known to be important in its closed conformation for NS2b ii) residues close to the active site, iii) several residues evenly spread on the NS2b-NS3 contact surface, and iv) some inner residues most likely related to the overall stability of the protease. In addition, we found concordance on our list of residues with previously identified amino acids part of a highly conserved peptide studied for vaccine development.
Universidad San Francisco de Quito, Grupo de Química Computacional y Teórica (QCT-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador.
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Aguilera-Pesantes
Universidad San Francisco de Quito, Grupo de Química Computacional y Teórica (QCT-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador.
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Robayo
Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador.
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Méndez
Universidad San Francisco de Quito, Grupo de Química Computacional y Teórica (QCT-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador.
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Mollocana
Universidad San Francisco de Quito, Grupo de Química Computacional y Teórica (QCT-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Grupo de Medicina Molecular y Traslacional (MeM&T), Escuela de Medicina, Colegio de Ciencias de la Salud (COCSA), Av.Interoceánica Km 12 ½ y Av. Florencia, 17-1200-841, Cumbayá, Quito, Ecuador.
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Marrero-Ponce
Universidad San Francisco de Quito, Grupo de Química Computacional y Teórica (QCT-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador.
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Torres
Universidad San Francisco de Quito, Grupo de Química Computacional y Teórica (QCT-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Instituto de Simulación Computacional (ISC-USFQ), Diego de Robles sn y Vía Interoceánica, 17-1200-841, Quito, Ecuador; Universidad San Francisco de Quito, Grupo de Medicina Molecular y Traslacional (MeM&T), Escuela de Medicina, Colegio de Ciencias de la Salud (COCSA), Av.Interoceánica Km 12 ½ y Av. Florencia, 17-1200-841, Cumbayá, Quito, Ecuador. Electronic address: mmendez@usfq.edu.ec.
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Méndez
D001665:Binding Sites; D003716:Dengue Virus / Q000201:enzymology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008956:Models, Chemical; D062105:Molecular Docking Simulation / Q000379:methods*; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D020539:Sequence Analysis, Protein / Q000379:methods*; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000648:ultrastructure*
D004791:Enzyme Inhibitors; C080102:NS2B protein, flavivirus; D017361:Viral Nonstructural Proteins
Bindability sites; Computational alanine scanning mutagenesis; DENV NS2b-NS3 protease; Dengue virus; Machine learning; Multilayer perceptron; Protease inhibitor