Discovery of novel dengue virus entry inhibitors via a structure-based approach

Abstract

Dengue is a mosquito-borne virus that has become a major public health concern worldwide in recent years. However, the current treatment for dengue disease is only supportive therapy, and no specific antivirals are available to control the infections. Therefore, the need for safe and effective antiviral drugs against this virus is of utmost importance. Entry of the dengue virus (DENV) into a host cell is mediated by its major envelope protein, E. The crystal structure of the E protein reveals a hydrophobic pocket occupied by the detergent n-octyl-β-d-glucoside (β-OG) lying at a hinge region between domains I and II, which is important for the low-pH-triggered conformational rearrangement required for fusion. Thus, the E protein is an attractive target for the development of antiviral agents. In this work, we performed prospective docking-based virtual screening to identify small molecules that likely bind to the β-OG binding site. Twenty-three structurally different compounds were identified and two of them had an EC value in the low micromolar range. In particular, compound 2 (EC=3.1μM) showed marked antiviral activity with a good therapeutic index. Molecular dynamics simulations were used in an attempt to characterize the interaction of 2 with protein E, thus paving the way for future ligand optimization endeavors. These studies highlight the possibility of using a new class of DENV inhibitors against dengue.

Structure-based drug design for envelope protein E2 uncovers a new class of bovine viral diarrhea inhibitors that block virus entry

“…In principle, site I was selected because it has the largest predicted pocket volumes (~700 Å 3 ) and resulted more appropriate for ligand binding (Figure 1). Docking-based virtual screening was performed using approximately 110,000 small-molecules from the Maybridge database to identify ligands of E2 (PDB code: 2YQ2, chain A) using the ICM software, which proved successful for finding hits on several other targets (Cavasotto et al, 2008;Cavasotto et al, 2006;Chan et al, 2013;Leal et al, 2017;Sun et al, 2014). An initial ADME filter (Jorgensen, 2005) was imposed, in order to retain only potentially non-toxic and druggable molecules.…”

Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2

“…Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in lead identification and optimization (Cavasotto and Orry, 2007 ; Jorgensen, 2009 ; Spyrakis and Cavasotto, 2015 ). Virus envelope proteins are attractive targets for the development of antiviral agents, and structure-based drug design has been successfully used to identify small molecule ligands of envelope proteins that block entry of flaviviruses (Zhou et al, 2008 ; Kampmann et al, 2009 ; Leal et al, 2017 ). With the aim of finding novel targets for pestivirus drug design, we focused on the in silico identification of antivirals directed against the envelope protein E2 of BVDV.…”

A fluorescence nanoscopy marker for corticotropin-releasing hormone type 1 receptor: computer design, synthesis, signaling effects, super-resolved fluorescence imaging, and in situ affinity constant in cells

“…3 The molecular system was described in the dihedral space using the ECEPP/3 force field 67,68 within the ICM program 36,37 and prepared in a similar fashion as in earlier works. [69][70][71] Docking was performed within the orthosteric binding site after deleting all water molecules and co-factors, using a flexible-ligand-rigid-receptor approach as implemented in ICM. In the docking algorithm the torsional degrees of freedom (DOF) of the smallmolecules and their six rigid coordinates were considered flexible within the receptor energy field, and subjected to a Monte Carlo global energy minimization.…”