Identification of a novel class of inhibitor of human and Escherichia coli thymidine phosphorylase by in silico screening

Enteroviruses are a ubiquitous mammalian pathogen that can produce mild to life-threatening disease. Bearing this in mind, we have developed a rapid, accurate and economical point-of-care biosensor that can detect a nucleic acid sequences conserved amongst 96% of all known enteroviruses. The biosensor harnesses the physicochemical properties of gold nanoparticles and aptamers to provide colourimetric, spectroscopic and lateral flow-based identification of an exclusive enteroviral RNA sequence (23 bases), which was identified through in silico screening. Aptamers were designed to demonstrate specific complementarity towards the target enteroviral RNA to produce aggregated gold-aptamer nanoconstructs. Conserved target enteroviral nucleic acid sequence (≥ 1x10-7 M, ≥1.4×10-14 g/mL), initiates gold-aptamer-nanoconstructs disaggregation and a signal transduction mechanism, producing a colourimetric and spectroscopic blueshift (544 nm (purple) > 524 nm (red)). Furthermore, lateral-flow-assays that utilise gold-aptamer-nanoconstructs were unaffected by contaminating human genomic DNA, demonstrated rapid detection of conserved target enteroviral nucleic acid sequence (< 60 s) and could be interpreted with a bespoke software and hardware electronic interface. We anticipate our methodology will translate in-silico screening of nucleic acid databases to a tangible enteroviral desktop detector, which could be readily translated to related organisms. This will pave-the-way forward in the clinical evaluation of disease and complement existing strategies at overcoming antimicrobial resistance.

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Molecular Mechanisms of Several Novel Dipeptides with Angiotensin-Iconverting Enzyme Inhibitory Activity from In-silico Screening of Silkworm Pupae Protein

Current Pharmaceutical Biotechnology ◽

10.2174/138920101508140930153336 ◽

2014 ◽

Vol 15 (8) ◽

pp. 691-699 ◽

Cited By ~ 2

Author(s):

Wei Wang ◽

Yu Zhang ◽

Nan Wang ◽

Zuoyi Zhu

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Molecular Mechanisms ◽

In Silico Screening ◽

Silkworm Pupae

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Design and in-silico screening of Peptide Nucleic Acid (PNA) inspired novel pronucleotide scaffolds targeting COVID-19

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200923143935 ◽

2020 ◽

Vol 16 ◽

Author(s):

Bichismita Sahu ◽

Santosh Kumar Behera ◽

Rudradip Das ◽

Tanay Dalvi ◽

Arnab Chowdhury ◽

...

Keyword(s):

Nucleic Acid ◽

In Silico ◽

Peptide Nucleic Acid ◽

Large Set ◽

Nonstructural Proteins ◽

In Silico Screening ◽

Replication Process ◽

Enveloped Virus ◽

Treatment Regimens ◽

Novel Coronavirus

Introduction: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned itself into a pandemic taking a heavy toll on human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive sense single-stranded enveloped virus and quite closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced. Methods: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes nonstructural proteins like RNA dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are in the advanced stage of clinical trials including Remdesivir. While performing close investigation of the large set of nucleic acid based drugs, we were surprised to find that the synthetic nucleic acid backbone is explored very little or rare. Results: We have designed scaffolds derived from peptide nucleic acid (PNA) and subjected them for in-silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess similar binding affinity as Remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 (12,000mg/kg) as opposed to Remdesivir (LD50 =1000mg/kg). Conclusion: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid derived compounds can serve as a leading scaffold to design, synthesize and evaluate many of similar compounds for the treatment of COVID-19.

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In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201119144535 ◽

2020 ◽

Vol 20 ◽

Author(s):

Dnyaneshwar Baswar ◽

Abha Sharma ◽

Awanish Mishra

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Silico ◽

Neurodegenerative Disorder ◽

Biological Activities ◽

Cholinergic Neurons ◽

In Silico Screening ◽

In Silico Studies ◽

Bbb Permeability ◽

Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

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In silico Screening and Molecular Interaction Studies of Tetrahydrocannabinol and its Derivatives with Acetylcholine Binding Protein

Current Chemical Biology ◽

10.2174/2212796812666180416145232 ◽

2018 ◽

Vol 12 (2) ◽

pp. 181-190 ◽

Cited By ~ 5

Author(s):

Priya P. Panigrahi ◽

Ramit Singla ◽

Ankush Bansal ◽

Moacyr Comar Junior ◽

Vikas Jaitak ◽

...

Keyword(s):

Molecular Interaction ◽

In Silico ◽

Binding Protein ◽

In Silico Screening ◽

Acetylcholine Binding Protein ◽

Interaction Studies

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In silico screening of drug candidates for thermoresponsive liposome formulations

Molecular Systems Design & Engineering ◽

10.1039/d0me00160k ◽

2021 ◽

Author(s):

Martin Balouch ◽

Martin Šrejber ◽

Marek Šoltys ◽

Petra Janská ◽

František Štěpánek ◽

...

Keyword(s):

In Silico ◽

Liposomal Formulation ◽

In Silico Screening ◽

Drug Candidates

In silico methodology for compound suitability for liposomal formulation has been developed. Water–lipid partitioning and permeation of candidate compounds from the DrugBank were calculated, and the most appropriate targets validated experimentally.

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In Silico Screening of Natural Products Isolated from Mexican Herbal Medicines against COVID-19

Biomolecules ◽

10.3390/biom11020216 ◽

2021 ◽

Vol 11 (2) ◽

pp. 216

Author(s):

Nadia A. Rivero-Segura ◽

Juan C. Gomez-Verjan

Keyword(s):

Natural Products ◽

In Silico ◽

Herbal Medicines ◽

In Silico Screening ◽

Docking Analysis ◽

Physiologically Based Pharmacokinetic ◽

Important Challenge ◽

Emodin Anthrone ◽

Therapeutic Tools ◽

Vaccine Distribution

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools.

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In silico molecular docking and in vitro antimicrobial efficacy of phytochemicals against multi-drug-resistant enteroaggregative Escherichia coli and non-typhoidal Salmonella spp.

Gut Pathogens ◽

10.1186/s13099-021-00443-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Padikkamannil Abishad ◽

Pollumahanti Niveditha ◽

Varsha Unni ◽

Jess Vergis ◽

Nitin Vasantrao Kurkure ◽

...

Keyword(s):

Escherichia Coli ◽

Molecular Docking ◽

In Silico ◽

Docking Studies ◽

Antimicrobial Efficacy ◽

Drug Resistant ◽

Protein Motifs ◽

Phytochemical Compounds ◽

In Silico Molecular Docking

Abstract Background In the wake of emergence of antimicrobial resistance, bioactive phytochemical compounds are proving to be important therapeutic agents. The present study envisaged in silico molecular docking as well as in vitro antimicrobial efficacy screening of identified phytochemical ligands to the dispersin (aap) and outer membrane osmoporin (OmpC) domains of enteroaggregative Escherichia coli (EAEC) and non-typhoidal Salmonella spp. (NTS), respectively. Materials and methods The evaluation of drug-likeness, molecular properties, and bioactivity of the identified phytocompounds (thymol, carvacrol, and cinnamaldehyde) was carried out using Swiss ADME, while Protox-II and StopTox servers were used to identify its toxicity. The in silico molecular docking of the phytochemical ligands with the protein motifs of dispersin (PDB ID: 2jvu) and outer membrane osmoporin (PDB ID: 3uu2) were carried out using AutoDock v.4.20. Further, the antimicrobial efficacy of these compounds against multi-drug resistant EAEC and NTS strains was determined by estimating the minimum inhibitory concentrations and minimum bactericidal concentrations. Subsequently, these phytochemicals were subjected to their safety (sheep and human erythrocytic haemolysis) as well as stability (cationic salts, and pH) assays. Results All the three identified phytochemicals ligands were found to be zero violators of Lipinski’s rule of five and exhibited drug-likeness. The compounds tested were categorized as toxicity class-4 by Protox-II and were found to be non- cardiotoxic by StopTox. The docking studies employing 3D model of dispersin and ompC motifs with the identified phytochemical ligands exhibited good binding affinity. The identified phytochemical compounds were observed to be comparatively stable at different conditions (cationic salts, and pH); however, a concentration-dependent increase in the haemolytic assay was observed against sheep as well as human erythrocytes. Conclusions In silico molecular docking studies provided useful insights to understand the interaction of phytochemical ligands with protein motifs of pathogen and should be used routinely before the wet screening of any phytochemicals for their antibacterial, stability, and safety aspects.

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