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Sruthi Unni

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Research paper thumbnail of Identification of a Potent Inhibitor Targeting the Spike Protein of Pandemic Human Coronavirus, SARS-CoV-2 by Computational Methods

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that... more Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative dru...

Research paper thumbnail of Identification of a repurposed drug as an inhibitor of Spike protein of human coronavirus SARS-CoV-2 by computational methods

Journal of Biosciences

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that... more Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein-ACE2 interface by making substantial p-p interactions with Tyr505 in the 'Site 1' hook region of RBD and hydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.

Research paper thumbnail of Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1

Research paper thumbnail of Human muscle pathology is associated with altered phosphoprotein profile of mitochondrial proteins in the skeletal muscle

Research paper thumbnail of Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2

Research paper thumbnail of Biochemical insight into pseudouridine synthase 7 (PUS7) as a novel interactor of sirtuin, SIRT1

Biochemical and Biophysical Research Communications

Research paper thumbnail of Rational discovery of a SOD1 tryptophan oxidation inhibitor with therapeutic potential for amyotrophic lateral sclerosis

Journal of Biomolecular Structure and Dynamics

Research paper thumbnail of The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Research paper thumbnail of Exploring novel antimicrobials targeting bacterial pyruvate formate lyase through pharmacophore based virtual screening

Research paper thumbnail of Identification of New Inhibitors for Human SIRT1: An in-silico Approach

Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 6, 2016

Background Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpre... more Background Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential. Objective The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method. Methodology We performed virtual screening using AutoDock Vina for the HDAC domain hSIRT1 against the DrugBank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an in-vitro deacetylase assay for selected compounds. Results Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and ...

Research paper thumbnail of Tryptophan Oxidation in the UQCRC1 Subunit of Mitochondrial Complex III (Ubiquinol-Cytochrome C Reductase) in a Mouse Model of Myodegeneration Causes Large Structural Changes in the Complex: A Molecular Dynamics Simulation Study

Scientific Reports, Jul 23, 2019

Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a c... more Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a cardiotoxin model of myodegeneration correlated muscle damage with mitochondrial dysfunction, which in turn entailed altered mitochondrial proteome and oxidative damage of mitochondrial proteins. Proteomic identification of oxidized proteins in muscle biopsies from muscular dystrophy patients and cardiotoxin model revealed specific mitochondrial proteins to be targeted for oxidation. These included respiratory complexes which displayed oxidative modification of Trp residues in different subunits. Among these, Ubiquinol-Cytochrome C Reductase Core protein 1 (UQCRC1), a subunit of Ubiquinol-Cytochrome C Reductase Complex or Cytochrome b-c1 Complex or Respiratory Complex III displayed oxidation of Trp395, which could be correlated with the lowered activity of Complex III. We hypothesized that Trp395 oxidation might contribute to altered local conformation and overall structure of Complex III, thereby potentially leading to altered protein activity. To address this, we performed molecular dynamics simulation of Complex III (oxidized at Trp395 of UQCRC1 vs. nonoxidized control). Molecular dynamic simulation analyses revealed local structural changes in the Trp395 site. Intriguingly, oxidized Trp395 contributed to decreased plasticity of Complex III due to significant cross-talk among the subunits in the matrix-facing region and subunits in the intermembrane space, thereby leading to impaired electron flow from cytochrome C. The skeletal muscle activity is critically dependent on the metabolic status, redox balance, and mitochondrial function 1. Studies in experimental models and human muscle biopsies have indicated that muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study 2 in a cardiotoxin (CTX) model of myodegeneration correlated with muscle damage and cell death with morphological and biochemical alterations in the

Research paper thumbnail of Identification of a Potent Inhibitor Targeting the Spike Protein of Pandemic Human Coronavirus, SARS-CoV-2 by Computational Methods

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that... more Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative dru...

Research paper thumbnail of Identification of a repurposed drug as an inhibitor of Spike protein of human coronavirus SARS-CoV-2 by computational methods

Journal of Biosciences

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that... more Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein-ACE2 interface by making substantial p-p interactions with Tyr505 in the 'Site 1' hook region of RBD and hydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.

Research paper thumbnail of Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1

Research paper thumbnail of Human muscle pathology is associated with altered phosphoprotein profile of mitochondrial proteins in the skeletal muscle

Research paper thumbnail of Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2

Research paper thumbnail of Biochemical insight into pseudouridine synthase 7 (PUS7) as a novel interactor of sirtuin, SIRT1

Biochemical and Biophysical Research Communications

Research paper thumbnail of Rational discovery of a SOD1 tryptophan oxidation inhibitor with therapeutic potential for amyotrophic lateral sclerosis

Journal of Biomolecular Structure and Dynamics

Research paper thumbnail of The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Research paper thumbnail of Exploring novel antimicrobials targeting bacterial pyruvate formate lyase through pharmacophore based virtual screening

Research paper thumbnail of Identification of New Inhibitors for Human SIRT1: An in-silico Approach

Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 6, 2016

Background Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpre... more Background Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential. Objective The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method. Methodology We performed virtual screening using AutoDock Vina for the HDAC domain hSIRT1 against the DrugBank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an in-vitro deacetylase assay for selected compounds. Results Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and ...

Research paper thumbnail of Tryptophan Oxidation in the UQCRC1 Subunit of Mitochondrial Complex III (Ubiquinol-Cytochrome C Reductase) in a Mouse Model of Myodegeneration Causes Large Structural Changes in the Complex: A Molecular Dynamics Simulation Study

Scientific Reports, Jul 23, 2019

Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a c... more Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a cardiotoxin model of myodegeneration correlated muscle damage with mitochondrial dysfunction, which in turn entailed altered mitochondrial proteome and oxidative damage of mitochondrial proteins. Proteomic identification of oxidized proteins in muscle biopsies from muscular dystrophy patients and cardiotoxin model revealed specific mitochondrial proteins to be targeted for oxidation. These included respiratory complexes which displayed oxidative modification of Trp residues in different subunits. Among these, Ubiquinol-Cytochrome C Reductase Core protein 1 (UQCRC1), a subunit of Ubiquinol-Cytochrome C Reductase Complex or Cytochrome b-c1 Complex or Respiratory Complex III displayed oxidation of Trp395, which could be correlated with the lowered activity of Complex III. We hypothesized that Trp395 oxidation might contribute to altered local conformation and overall structure of Complex III, thereby potentially leading to altered protein activity. To address this, we performed molecular dynamics simulation of Complex III (oxidized at Trp395 of UQCRC1 vs. nonoxidized control). Molecular dynamic simulation analyses revealed local structural changes in the Trp395 site. Intriguingly, oxidized Trp395 contributed to decreased plasticity of Complex III due to significant cross-talk among the subunits in the matrix-facing region and subunits in the intermembrane space, thereby leading to impaired electron flow from cytochrome C. The skeletal muscle activity is critically dependent on the metabolic status, redox balance, and mitochondrial function 1. Studies in experimental models and human muscle biopsies have indicated that muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study 2 in a cardiotoxin (CTX) model of myodegeneration correlated with muscle damage and cell death with morphological and biochemical alterations in the

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