11 results on '"Seketoulie Keretsu"'
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2. Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
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Seketoulie Keretsu, Suparna Ghosh, and Seung Joo Cho
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Medicine ,Science - Abstract
Abstract Janus kinases (JAKs) are a family of non-receptor kinases that play a key role in cytokine signaling and their aberrant activities are associated with the pathogenesis of various immune diseases. The JAK1 isoform plays an essential role in the types 1 and II interferon signaling and elicits signals from the interleukin-2, interleukin-4, gp130, and class 2 receptor families. It is ubiquitously expressed in humans and its overexpression has been linked with autoimmune diseases such as myeloproliferative neoplasm. Although JAK1 inhibitors such as Tofacitinib have been approved for medical use, the low potency and off-target effects of these inhibitors have limited their use and calls for the development of novel JAK1 inhibitors. In this study, we used computational methods on a series of pyrrolopyridine derivatives to design new JAK1 inhibitors. Molecular docking and molecular dynamics simulation methods were used to study the protein-inhibitor interactions. 3D-quantitative structure–activity relationship models were developed and were used to predict the activity of newly designed compounds. Free energy calculation methods were used to study the binding affinity of the inhibitors with JAK1. Of the designed compounds, seventeen of the compounds showed a higher binding energy value than the most active compound in the dataset and at least six of the compounds showed higher binding energy value than the pan JAK inhibitor Tofacitinib. The findings made in this study could be utilized for the further development of JAK1 inhibitors.
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- 2021
- Full Text
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3. Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using docking, molecular dynamics, and 3D-QSAR
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Suparna Ghosh, Seketoulie Keretsu, and Seung Joo Cho
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Rho-associated kinase-1 (ROCK1) ,Cardio-vascular disease ,Molecular docking ,Molecular dynamics ,MMPBSA ,3D-QSAR ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity of ROCK phosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted molecular modeling techniques such as docking, molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of N-ethyl-4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q2 = 0.774, r2 = 0.965, ONC = 6, and ${r}_{pred}^{2}$ r p r e d 2 = 0.703) and CoMSIA (q2 = 0.676, r2 = 0.949, ONC = 6, and ${r}_{pred}^{2}$ r p r e d 2 = 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors.
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- 2021
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4. Molecular Modeling Studies of N-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
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Suparna Ghosh, Seketoulie Keretsu, and Seung Joo Cho
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FMS-like tyrosine kinase-3 ,acute myeloid leukemia ,MD simulation ,binding free energy ,3D-QSAR ,CoMFA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure–activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison–Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (q2 = 0.802, r2 = 0.983, and QF32 = 0.698) and CoMSIA (q2 = 0.725, r2 = 0.965 and QF32 = 0.668) established the structure–activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC50 values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.
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- 2021
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5. Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors
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Swapnil P. Bhujbal, Seketoulie Keretsu, and Seung Joo Cho
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RET ,receptor tyrosine kinases ,inhibitors ,pyrazole ,3D-QSAR ,MM/PBSA ,Organic chemistry ,QD241-441 - Abstract
RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure–activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.
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- 2021
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6. Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors
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Seketoulie Keretsu, Suparna Ghosh, and Seung Joo Cho
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c-KIT ,PDGFRα ,molecular dynamics simulation ,free energy calculation ,CoMFA ,CoMSIA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Gastrointestinal stromal tumors (GISTs) are the most common Mesenchymal Neoplasm of the gastrointestinal tract. The tumorigenesis of GISTs has been associated with the gain-of-function mutation and abnormal activation of the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor alpha (PDGFRα) kinases. Hence, inhibitors that target c-KIT and PDGFRα could be a therapeutic option for the treatment of GISTs. The available approved c-KIT/PDGFRα inhibitors possessed low efficacy with off-target effects, which necessitated the development of potent inhibitors. We performed computational studies of 48 pyrazolopyridine derivatives that showed inhibitory activity against c-KIT and PDGFRα to study the structural properties important for inhibition of both the kinases. The derivative of phenylurea, which has high activities for both c-KIT (pIC50 = 8.6) and PDGFRα (pIC50 = 8.1), was used as the representative compound for the dataset. Molecular docking and molecular dynamics simulation (100 ns) of compound 14 was performed. Compound 14 showed the formation of hydrogen bonding with Cys673, Glu640, and Asp810 in c-KIT, and Cys677, Glu644, and Asp836 in PDGFRα. The results also suggested that Thr670/T674 substitution in c-KIT/PDGFRα induced conformational changes at the binding site of the receptors. Three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed based on the inhibitors. Contour map analysis showed that electropositive and bulky substituents at the para-position and the meta-position of the benzyl ring of compound 14 was favorable and may increase the inhibitory activity against both c-KIT and PDGFRα. Analysis of the results suggested that having bulky and hydrophobic substituents that extend into the hydrophobic pocket of the binding site increases the activity for both c-KIT and PDGFRα. Based on the contour map analysis, 50 compounds were designed, and the activities were predicted. An evaluation of binding free energy showed that eight of the designed compounds have potential binding affinity with c-KIT/PDGFRα. Absorption, distribution, metabolism, excretion and toxicity (ADMET) and synthetic feasibility tests showed that the designed compounds have reasonable pharmaceutical properties and synthetic feasibility. Further experimental study of the designed compounds is recommended. The structural information from this study could provide useful insight into the future development of c-KIT and PDGFRα inhibitors.
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- 2020
- Full Text
- View/download PDF
7. Molecular Modeling Studies of N-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
- Author
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Seung Joo Cho, Suparna Ghosh, and Seketoulie Keretsu
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CoMFA ,Molecular model ,Stereochemistry ,QH301-705.5 ,acute myeloid leukemia ,Molecular mechanics ,Catalysis ,Inorganic Chemistry ,Molecular dynamics ,Physical and Theoretical Chemistry ,Tyrosine ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,binding free energy ,3D-QSAR ,biology ,Chemistry ,Organic Chemistry ,Active site ,MD simulation ,General Medicine ,Ligand (biochemistry) ,Computer Science Applications ,Docking (molecular) ,FMS-like tyrosine kinase-3 ,Fms-Like Tyrosine Kinase 3 ,biology.protein ,CoMSIA - Abstract
Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure–activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison–Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (q2 = 0.802, r2 = 0.983, and QF32 = 0.698) and CoMSIA (q2 = 0.725, r2 = 0.965 and QF32 = 0.668) established the structure–activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC50 values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.
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- 2021
- Full Text
- View/download PDF
8. Supplementary Files of 'Computational Modeling of FLT3 inhibitors'
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Suparna Ghosh, Seketoulie Keretsu, and Seung Joo Cho
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Topology and Parameters ,Molecular Dynamics ,Protein-ligand complex ,Docking ,Gromacs script - Abstract
Title:Docking, Molecular dynamics, and 3D-QSAR study of N-phenylpyrimidine-4-amine based compounds showed the potential chemical group modification strategies for the inhibition of FMS-like tyrosine kinase-3 The ZIP file contains all the protein-ligand docked complex, input/output files, ligand topology-parameter files, force field, and running scripts used in the above study.
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- 2021
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- View/download PDF
9. Computational study of paroxetine-like inhibitors reveals new molecular insight to inhibit GRK2 with selectivity over ROCK1
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Seketoulie Keretsu, Swapnil P. Bhujbal, and Seung Joo Cho
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0301 basic medicine ,Quantitative structure–activity relationship ,Computational chemistry ,G-Protein-Coupled Receptor Kinase 2 ,Stereochemistry ,Quantitative Structure-Activity Relationship ,lcsh:Medicine ,Plasma protein binding ,Pyrazole ,Molecular Dynamics Simulation ,Molecular Docking Simulation ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Catalytic Domain ,Humans ,Computational models ,Binding site ,lcsh:Science ,Protein Kinase Inhibitors ,rho-Associated Kinases ,Multidisciplinary ,Binding Sites ,biology ,Molecular Structure ,Hydrogen bond ,Kinase ,Beta adrenergic receptor kinase ,lcsh:R ,Hydrogen Bonding ,Enzyme Activation ,Paroxetine ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Drug Design ,Computer modelling ,biology.protein ,lcsh:Q ,Structure-based drug design ,Hydrophobic and Hydrophilic Interactions ,Algorithms ,Protein Binding - Abstract
The G-protein coupled receptor kinase 2 (GRK2) regulates the desensitization of beta-adrenergic receptors (β-AR), and its overexpression has been implicated in heart failure. Hence, the inhibition of GRK2 is considered to be an important drug target for the treatment of heart failure. Due to the high sequence similarity of GRK2 with the A, G, and C family (AGC family) of kinases, the inhibition of GRK2 also leads to the inhibition of AGC kinases such as Rho-associated coiled-coil kinase 1 (ROCK1). Therefore, unraveling the mechanisms to selectively inhibit GRK2 poses an important challenge. We have performed molecular docking, three dimensional quantitative structure activity relationship (3D-QSAR), molecular dynamics (MD) simulation, and free energy calculations techniques on a series of 53 paroxetine-like compounds to understand the structural properties desirable for enhancing the inhibitory activity for GRK2 with selectivity over ROCK1. The formation of stable hydrogen bond interactions with the residues Phe202 and Lys220 of GRK2 seems to be important for selective inhibition of GRK2. Electropositive substituents at the piperidine ring and electronegative substituents near the amide linker between the benzene ring and pyrazole ring showed a higher inhibitory preference for GRK2 over ROCK1. This study may be used in designing more potent and selective GRK2 inhibitors for therapeutic intervention of heart failure.
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- 2019
10. Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors
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Suparna Ghosh, Seketoulie Keretsu, and Seung Joo Cho
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Models, Molecular ,PDGFRα ,Receptor, Platelet-Derived Growth Factor alpha ,Stromal cell ,CoMFA ,Molecular model ,Gastrointestinal Stromal Tumors ,Pyridines ,Quantitative Structure-Activity Relationship ,Antineoplastic Agents ,Stem cell factor ,Article ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,Growth factor receptor ,c-KIT ,Pyrazolopyridine ,free energy calculation ,Humans ,Physical and Theoretical Chemistry ,Binding site ,Receptor ,Protein Kinase Inhibitors ,Molecular Biology ,neoplasms ,lcsh:QH301-705.5 ,Spectroscopy ,Gastrointestinal Neoplasms ,3D-QSAR ,Binding Sites ,Chemistry ,Kinase ,Organic Chemistry ,General Medicine ,digestive system diseases ,Computer Science Applications ,Molecular Docking Simulation ,Proto-Oncogene Proteins c-kit ,molecular dynamics simulation ,Amino Acid Substitution ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research ,Pyrazoles ,Mutant Proteins ,Drug Screening Assays, Antitumor ,CoMSIA - Abstract
Gastrointestinal stromal tumors (GISTs) are the most common Mesenchymal Neoplasm of the gastrointestinal tract. The tumorigenesis of GISTs has been associated with the gain-of-function mutation and abnormal activation of the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor alpha (PDGFR&alpha, ) kinases. Hence, inhibitors that target c-KIT and PDGFR&alpha, could be a therapeutic option for the treatment of GISTs. The available approved c-KIT/PDGFR&alpha, inhibitors possessed low efficacy with off-target effects, which necessitated the development of potent inhibitors. We performed computational studies of 48 pyrazolopyridine derivatives that showed inhibitory activity against c-KIT and PDGFR&alpha, to study the structural properties important for inhibition of both the kinases. The derivative of phenylurea, which has high activities for both c-KIT (pIC50 = 8.6) and PDGFR&alpha, (pIC50 = 8.1), was used as the representative compound for the dataset. Molecular docking and molecular dynamics simulation (100 ns) of compound 14 was performed. Compound 14 showed the formation of hydrogen bonding with Cys673, Glu640, and Asp810 in c-KIT, and Cys677, Glu644, and Asp836 in PDGFR&alpha, The results also suggested that Thr670/T674 substitution in c-KIT/PDGFR&alpha, induced conformational changes at the binding site of the receptors. Three-dimensional quantitative structure&ndash, activity relationship (3D-QSAR) models were developed based on the inhibitors. Contour map analysis showed that electropositive and bulky substituents at the para-position and the meta-position of the benzyl ring of compound 14 was favorable and may increase the inhibitory activity against both c-KIT and PDGFR&alpha, Analysis of the results suggested that having bulky and hydrophobic substituents that extend into the hydrophobic pocket of the binding site increases the activity for both c-KIT and PDGFR&alpha, Based on the contour map analysis, 50 compounds were designed, and the activities were predicted. An evaluation of binding free energy showed that eight of the designed compounds have potential binding affinity with c-KIT/PDGFR&alpha, Absorption, distribution, metabolism, excretion and toxicity (ADMET) and synthetic feasibility tests showed that the designed compounds have reasonable pharmaceutical properties and synthetic feasibility. Further experimental study of the designed compounds is recommended. The structural information from this study could provide useful insight into the future development of c-KIT and PDGFR&alpha, inhibitors.
- Published
- 2020
11. Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation
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Seketoulie Keretsu, Swapnil P. Bhujbal, and Seung Joo Cho
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Aminoisobutyric Acids ,Databases, Factual ,Proline ,medicine.medical_treatment ,Pneumonia, Viral ,COVID-19 ,Computational models ,Virtual drug screening ,Druggability ,lcsh:Medicine ,Computational biology ,Molecular Dynamics Simulation ,Viral Nonstructural Proteins ,medicine.disease_cause ,Article ,Betacoronavirus ,Leucine ,medicine ,Humans ,Protease inhibitor (pharmacology) ,Protease Inhibitors ,Aclarubicin ,lcsh:Science ,Pandemics ,Coronavirus 3C Proteases ,Coronavirus ,Protease ,Multidisciplinary ,Binding Sites ,Chemistry ,Drug discovery ,SARS-CoV-2 ,lcsh:R ,Hydrogen Bonding ,Molecular Docking Simulation ,Cysteine Endopeptidases ,Thiazoles ,Faldaprevir ,Quinolines ,Thermodynamics ,lcsh:Q ,Coronavirus Infections ,Saquinavir ,Oligopeptides ,MEROPS ,medicine.drug - Abstract
In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CLpro inhibitor and the availability of the X-ray crystal structure of 3CLpro (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CLpro inhibitors from the protease inhibitor database MEROPS (https://www.ebi.ac.uk/merops/index.shtml). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CLpro inhibitors. We recommend further experimental investigation of these compounds.
- Published
- 2020
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