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Journal ArticleDOI

Identification of dengue viral RNA-dependent RNA polymerase inhibitor using computational fragment-based approaches and molecular dynamics study.

TL;DR: A cascade of methods, fragment screening, fragment growing, and fragment linking revealed the compound [2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl]8-(1,3-benzothiazol-2-yl)naphthalene- 1-carboxylate as a potent dengue viral polymerase inhibitor.
Abstract: Dengue is a major public health concern in tropical and subtropical countries of the world There are no specific drugs available to treat dengue Even though several candidates targeted both viral and host proteins to overcome dengue infection, they have not yet entered into the later stages of clinical trials In order to design a drug for dengue fever, newly emerged fragment-based drug designing technique was applied RNA-dependent RNA polymerase, which is essential for dengue viral replication is chosen as a drug target for dengue drug discovery A cascade of methods, fragment screening, fragment growing, and fragment linking revealed the compound [2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl]8-(1,3-benzothiazol-2-yl)naphthalene-1-carboxylate as a potent dengue viral polymerase inhibitor Both strain energy and binding free energy calculations predicted that this could be a better inhibitor than the existing ones Molecular dynamics simulation studies showed that the dengue polymerase-lead complex is stable and their interactions are consistent throughout the simulation The hydrogen-bonded interactions formed by the residues Arg792, Thr794, Ser796, and Asn405 are the primary contributors for the stability and the rigidity of the polymerase-lead complex This might keep the polymerase in closed conformation and thus inhibits viral replication Hence, this might be a promising lead molecule for dengue drug designing Further optimization of this lead molecule would result in a potent drug for dengue
Citations
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Journal ArticleDOI
28 Dec 2020
TL;DR: Novel compounds are proposed, which may act as potential drugs against DENV by inhibiting HKII’s activity by using the computational studies.
Abstract: Dengue fever, which is a disease caused by the dengue virus (DENV), is a major unsolved issue in many tropical and sub-tropical regions of the world. The absence of treatment that effectively prevent further viral propagation inside the human’s body resulted in a high number of deaths globally each year. Thus, novel anti-dengue therapies are required for effective treatment. Hu-man hexokinase II (HKII), which is the first enzyme in the glycolytic pathway, is an important drug target due to its significant impact on viral replication and survival in host cells. In this study, 23.1 million compounds were computationally-screened against HKII using the Ultrafast Shape Recognition with a CREDO Atom Types (USRCAT) algorithm. In total, 300 compounds with the highest similarity scores relative to three reference molecules, known as Al-pha-D-glucose (GLC), Beta-D-glucose-6-phosphate (BG6), and 2-deoxyglucose (2DG), were aligned. Of these 300 compounds, 165 were chosen for further structure-based screening, based on their similarity scores, ADME analysis, the Lipinski’s Rule of Five, and virtual toxicity test results. The selected analogues were subsequently docked against each domain of the HKII structure (PDB ID: 2NZT) using AutoDock Vina programme. The three top-ranked compounds for each query were then selected from the docking results based on their binding energy, the number of hydrogen bonds formed, and the specific catalytic residues. The best docking results for each analogue were observed for the C-terminus of Chain B. The top-ranked analogues of GLC, compound 10, compound 26, and compound 58, showed predicted binding energies of −7.2, −7.0, and −6.10 kcal/mol and 7, 5, and 2 hydrogen bonds, respectively. The analogues of BG6, compound 30, compound 36, and compound 38, showed predicted binding energies of −7.8, −7.4, and −7.0 kcal/mol and 11, 9, and 5 hydrogen bonds, while the top three analogues of 2DG, known as compound 1, compound 4, and compound 31, showed predicted binding energies of −6.8, −6.3, and −6.3 kcal/mol and 4, 3, and 1 hydrogen bonds, sequentially. The highest-ranked compounds in the docking analysis were then selected for molecular dynamics simulation, where compound 10, compound 30, and compound 1, which are the analogues of GLC, BG6, and 2DG, have shown strong protein-ligand stability with an RMSD value of ±5.0 A° with a 5 H bond, ±4.0 A° with an 8 H bond, and ±0.5 A° with a 2 H bond, respectively, compared to the reference molecules throughout the 20 ns simulation time. Therefore, by using the computational studies, we pro-posed novel compounds, which may act as potential drugs against DENV by inhibiting HKII’s activity.

335 citations

Journal ArticleDOI
TL;DR: The crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution is described as a platform for structure-based drug design strategy and shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.
Abstract: The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 A resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution. The Zika virus outbreak is a global health threat and there is an urgent need for drugs against the virus. Here the authors present the structure of the RNA-dependent RNA-polymerase domain from Zika non-structural protein 5, which is a template for the design of non-nucleoside polymerase inhibitors.

87 citations

Journal ArticleDOI
TL;DR: The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays.
Abstract: The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis’ fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.

76 citations

Journal ArticleDOI
TL;DR: This in silico ‘per-residue energy decomposition pharmacophore’ virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.
Abstract: The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This in silico 'per-residue energy decomposition pharmacophore' virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.

56 citations


Cites background from "Identification of dengue viral RNA-..."

  • ...The human body does not contain an RdRp enzyme or analogs of it, thus inhibitors may not cause severe toxic effects, making it an optimal target in drug design (Shanmugam et al., 2016)....

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Journal Article
TL;DR: In this article, an optimized and proven screening technique was used in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase.
Abstract: The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This in silico 'per-residue energy decomposition pharmacophore' virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.

50 citations

References
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Journal ArticleDOI
TL;DR: It is shown that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets.
Abstract: Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.

3,658 citations

Journal ArticleDOI
TL;DR: Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input.
Abstract: Epik is a computer program for predicting pKa values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein–ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed.

1,309 citations

Journal ArticleDOI
TL;DR: The underlying biology of BRAF, the technology used to identify vemurafenib and its clinical development milestones, along with future prospects based on lessons learned during its development are described.
Abstract: The identification of driver oncogenes has provided important targets for drugs that can change the landscape of cancer therapies. One such example is the BRAF oncogene, which is found in about half of all melanomas as well as several other cancers. As a druggable kinase, oncogenic BRAF has become a crucial target of small-molecule drug discovery efforts. Following a rapid clinical development path, vemurafenib (Zelboraf; Plexxikon/Roche) was approved for the treatment of BRAF-mutated metastatic melanoma in the United States in August 2011 and the European Union in February 2012. This Review describes the underlying biology of BRAF, the technology used to identify vemurafenib and its clinical development milestones, along with future prospects based on lessons learned during its development.

662 citations


"Identification of dengue viral RNA-..." refers background in this paper

  • ...An anticancer drug Zelboraf (Vemurafenib) approved by FDA is a milestone in the success history of FBDD (Bollag et al., 2012)....

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  • ...Fragment-based drug designing (FBDD) has emerged as an efficient method in drug discovery and design....

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  • ...This makes GFL suitable for FBDD and was downloaded from Enamine database in structure data file format (sdf)....

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  • ...The availability of suitable high-throughput screening approaches, sensitive biophysical techniques such as nuclear magnetic resonance and X-ray crystallography and best optimization strategies makes FBDD a powerful tool for finding good quality hits for a wide range of drug targets (Kumar, Voet, & Zhang, 2012)....

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  • ...We applied FBDD technique and identified a potent inhibitor for DV RdRp enzyme....

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Journal ArticleDOI
TL;DR: Viable methods now exist for predictions with less than 1 log unit uncertainty, which is adequate for prescreening synthetic candidates or design of combinatorial libraries, which would require an experimental database of highly accurate solubilities for a large, diverse collection of drug-like molecules.

660 citations

Journal ArticleDOI
TL;DR: How phylogenetics have improved understanding of DENV population dynamics and sizes at various stages of infection and transmission is examined, and how this information may influence pathogenesis and improve the ability to understand and predict DENV emergence is examined.

399 citations


"Identification of dengue viral RNA-..." refers background in this paper

  • ...Four closely related but antigenically distinct serotypes of dengue virus (DV 1-4) causes dengue infection (Weaver & Vasilakis, 2009)....

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