Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies.
J Mol Graph Model. 2018 01; 79:88-102.JM

Abstract

Dengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of Dengue virus. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group. In this study, in order to investigate the effect of extended time of molecular dynamics (MD) simulations on structural and dynamical profiles of used complexes, simulation run time is increased from 50-ns to 100-ns for the each system. In addition, a well-known Dengue virus inhibitor (MB21) from literature is used as reference structure (positive control) to compare the proposed molecules. Post-processing MD analyses including Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations were conducted to predict binding free energies of inhibitors from derived trajectory frames of MD simulations. Identified compounds are further directed to Quantum-Polarized Ligand Docking (QPLD), molecular fingerprint-based virtual screening of another small molecule database (Otava Drug Like small molecule database), and Structure-based Pharmacophore Modeling (E-Pharmacophore). Finally, cell proliferation and cytotoxicity tests as well as pre- and post-treatment on HUH7 cells infected with DENV2 NGC strain are applied for four identified hit molecules (ZINC36681949, ZINC44921800, ZINC95518765 and ZINC39500661) to check whether these drugs inhibit DENV2 from entry and/or exit pathways. Based on cell-based Dengue quantification assays, there is no effect seen on pre-treatment of cells with these compounds indicating that the early infection processes of virus is not affected. In contrast, the post-treatment of cells with these compounds after Dengue virus infection has resulted in a significant 1 log PFU/ml reduction of the virus infectious titre.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Mirza SB

Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey; Research Laboratory of Electronics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Department of Biosciences, COMSATS Institute of Information Technology (CIIT), Park Road, Chak Shahzad, Islamabad, Pakistan.

Lee RCH

Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.

Chu JJH

Salmas RE

Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.

Mavromoustakos T

Kapodistrian University of Athens, Department of Chemistry, Athens, Greece.

Durdagi S

Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.

MeSH

Antiviral AgentsDengue VirusDrug DesignDrug DiscoveryDrug Evaluation, PreclinicalHumansHydrogen BondingMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationQuantitative Structure-Activity RelationshipSmall Molecule LibrariesViral Nonstructural Proteins

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29156382

Citation

Mirza, Shaher Bano, et al. "Discovery of Selective Dengue Virus Inhibitors Using Combination of Molecular Fingerprint-based Virtual Screening Protocols, Structure-based Pharmacophore Model Development, Molecular Dynamics Simulations and in Vitro Studies." Journal of Molecular Graphics & Modelling, vol. 79, 2018, pp. 88-102.

Mirza SB, Lee RCH, Chu JJH, et al. Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies. J Mol Graph Model. 2018;79:88-102.

Mirza, S. B., Lee, R. C. H., Chu, J. J. H., Salmas, R. E., Mavromoustakos, T., & Durdagi, S. (2018). Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies. Journal of Molecular Graphics & Modelling, 79, 88-102. https://doi.org/10.1016/j.jmgm.2017.10.010

Mirza SB, et al. Discovery of Selective Dengue Virus Inhibitors Using Combination of Molecular Fingerprint-based Virtual Screening Protocols, Structure-based Pharmacophore Model Development, Molecular Dynamics Simulations and in Vitro Studies. J Mol Graph Model. 2018;79:88-102. PubMed PMID: 29156382.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies. AU - Mirza,Shaher Bano, AU - Lee,Regina Ching Hua, AU - Chu,Justin Jang Hann, AU - Salmas,Ramin Ekhteiari, AU - Mavromoustakos,Thomas, AU - Durdagi,Serdar, Y1 - 2017/10/24/ PY - 2017/11/21/pubmed PY - 2019/9/19/medline PY - 2017/11/21/entrez KW - Anti-dengue drugs KW - Cell proliferation KW - Cytotoxicity tests KW - DENV2 NGC strain KW - Dengue KW - Molecular dynamics SP - 88 EP - 102 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 79 N2 - Dengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of Dengue virus. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group. In this study, in order to investigate the effect of extended time of molecular dynamics (MD) simulations on structural and dynamical profiles of used complexes, simulation run time is increased from 50-ns to 100-ns for the each system. In addition, a well-known Dengue virus inhibitor (MB21) from literature is used as reference structure (positive control) to compare the proposed molecules. Post-processing MD analyses including Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations were conducted to predict binding free energies of inhibitors from derived trajectory frames of MD simulations. Identified compounds are further directed to Quantum-Polarized Ligand Docking (QPLD), molecular fingerprint-based virtual screening of another small molecule database (Otava Drug Like small molecule database), and Structure-based Pharmacophore Modeling (E-Pharmacophore). Finally, cell proliferation and cytotoxicity tests as well as pre- and post-treatment on HUH7 cells infected with DENV2 NGC strain are applied for four identified hit molecules (ZINC36681949, ZINC44921800, ZINC95518765 and ZINC39500661) to check whether these drugs inhibit DENV2 from entry and/or exit pathways. Based on cell-based Dengue quantification assays, there is no effect seen on pre-treatment of cells with these compounds indicating that the early infection processes of virus is not affected. In contrast, the post-treatment of cells with these compounds after Dengue virus infection has resulted in a significant 1 log PFU/ml reduction of the virus infectious titre. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/29156382/Discovery_of_selective_dengue_virus_inhibitors_using_combination_of_molecular_fingerprint_based_virtual_screening_protocols_structure_based_pharmacophore_model_development_molecular_dynamics_simulations_and_in_vitro_studies_ DB - PRIME DP - Unbound Medicine ER -

Tags

Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies.J Mol Graph Model. 2018 01; 79:88-102.JM