Drug repurposing using similarity-based target prediction, docking studies and scaffold hopping of lefamulin

2020 ◽  
Vol 17 ◽  
Author(s):  
Shikha Sharma ◽  
Shweta Sharma ◽  
Vaishali Pathak ◽  
Parwinder Kaur ◽  
Rajesh Kumar Singh
Keyword(s):  
In Silico ◽  
Target Prediction ◽  
Drug Repurposing ◽  
Docking Studies ◽  
Target Protein ◽  
Future Perspective ◽  
Antibacterial Drug ◽  
Scaffold Hopping ◽  
Target Proteins ◽  
Renin Inhibitors

Aim: To investigate and validate the potential target proteins for drug repurposing of newly FDA approved antibacterial drug. Background: Drug repurposing is the process of assigning indications for drugs other than the one(s) that they were initially developed for. Discovery of entirely new indications from already approved drugs is highly lucrative as it minimizes the pipeline of the drug development process by reducing time and cost. In silico driven technologies made it possible to analyze molecules for different target proteins which are not yet explored. Objective: To analyze possible targets proteins for drug repurposing of lefamulin and their validation. Also, in silico prediction of novel scaffolds from lefamulin has been performed for assisting medicinal chemists in future drug design. Methods: A similarity-based prediction tool was employed for predicting target protein and further investigated using docking studies on PDB ID: 2V16. Besides, various in silico tools were employed for prediction of novel scaffolds from lefamulin using scaffold hopping technique followed by evaluation with various in silico parameters viz., ADME, synthetic accessibility and PAINS. Results: Based on the similarity and target prediction studies, renin is found as the most probable target protein for lefamulin. Further, validation studies using docking of lefamulin revealed the significant interactions of lefamulin with the binding pocket of the target protein. Also, three novel scaffolds were predicted using scaffold hopping technique and found to be in the limit to reduce the chances of drug failure in the physiological system during the last stage approval process. Conclusion: To encapsulate the future perspective, lefamulin may assist in the development of the renin inhibitors and, also three possible novel scaffolds with good pharmacokinetic profile can be developed into both as renin inhibitors and for bacterial infections.

scholarly journals IN SILICO STUDIES ON FUNCTIONALIZED AZAGLYCINE DERIVATIVES CONTAINING 2, 4-THIAZOLIDINEDIONE SCAFFOLD ON MULTIPLE TARGETS

2017 ◽  
Vol 9 (8) ◽  
pp. 209 ◽  
Author(s):  
Arifa Begum ◽  
Shaheen Begum ◽  
Prasad Kvsrg ◽  
Bharathi K.
Keyword(s):  
Molecular Docking ◽  
Oral Bioavailability ◽  
In Silico ◽  
Viral Infections ◽  
Target Prediction ◽  
Docking Studies ◽  
Antidiabetic Activity ◽  
Molecular Docking Studies ◽  
In Silico Studies ◽  
Glycine Derivative

Objective: The 2, 4-thiazolidinedione containing compounds could lead to most promising scaffolds with higher efficiency toward the targets recognized for its antidiabetic activity when combined with azaglycine moiety. The objective of the present work was to merge functionalized aza glycines with 2, 4-thiazolidinediones, perform in silico evaluation by molecular properties prediction and undertake the molecular docking studies with targets relevant to diabetes, bacterial and viral infections using Swiss Dock programme for unraveling the target identification which can be used for further designing.Methods: (i) In silico studies were performed using Molinspiration online tool, Swiss ADME website and Swiss Target Prediction websites to compute the physicochemical descriptors, oral bioavailability and brain penetration. (ii) Molecular docking studies were performed using Swiss Dock web service for enumeration of binding affinities and assess their biological potentiality.Results: The results predicted good drug likeness, solubility, permeability and oral bioavailability for the compounds. All the compounds showed good docking scores as compared to the reference drugs. The N-oleoyl functionalized aza glycine derivative demonstrated superior binding properties towards all the studied target reference proteins, suggesting its significance in pharmacological actions.Conclusion: The binding interactions observed in the molecular docking studies suggest good binding affinity of the oleoyl functionalized aza glycine derivative, indicating that this derivative would be a promising lead for further investigations of anti-viral, anti-inflammatory and anti-diabetic activities.

scholarly journals Design, Molecular Docking And In Silico Analysis Of Analogues Of Chloroquine And Hydroxychloroquine Against SARs-COV-2 Target (6w63.pdb)

2020 ◽  
Author(s):  
Naruka Solomon Yakubu ◽  
Olanike Catherine Poyi ◽  
Ezikiel Olabisi Afolabi
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Target Prediction ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Biologically Active ◽  
Dynamic Simulations ◽  
Comparable Activity ◽  
Silico Analysis

Abstract Computer-aided drug design has been an effective strategy and approach to discover, develop, analyze, accelerate and economize design and development of drugs and biologically active molecules. A total of twelve analogues of chloroquine (CQ) and hydroxychloroquine (HCQ) were designed and virtually analyzed using PyRx software, Molinspiration, Swiss ADME, Swiss-Target Prediction software and ProTox-II-Prediction of toxicity platform. Based on the docking studies carried out using Autodock vina, five analogues; H-368 (-6.0 Kcal/mol), H-372 (--6.0 Kcal/mol), H-156 (-5.9 Kcal/mol), H-139 (-5.7 Kcal/mol), C-136 (-5.7 Kcal/mol) exhibited higher binding affinity compared to HCQ(-5.5 Kcal/mol), while all twelve analogues exhibited higher binding affinity compared to CQ (-4.5Kcal/mol). In silico analysis of toxicity profile of this analogues shows a lower potential to toxicity and a comparable activity on some major isoforms of cytochrome P450. But unlike the parent molecules, both H-139 and H-156 are substrates of P-glycoproteins (P-gp) which implies that these analogues possess high clearance and less pharmacokinetic-related drug-drug interactions compared to the parent molecules. Herein we propose these analogues as potential inhibitors or lead compounds against the coronavirus with a view of conducting more molecular dynamic simulations, synthesizing and conducting in vitro studies on them.

scholarly journals Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1166
Author(s):  
Krishnaprasad Baby ◽  
Swastika Maity ◽  
Chetan H. Mehta ◽  
Akhil Suresh ◽  
Usha Y. Nayak ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Active Site ◽  
In Silico ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Rna Dependent Rna Polymerase ◽  
Target Proteins ◽  
Dynamics Simulations ◽  
Preclinical And Clinical Studies ◽  
And Control

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (Mpro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.

scholarly journals De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as Anti-Alzheimer’s Agents

2020 ◽  
Vol 16 (1) ◽  
pp. 54-72 ◽  
Author(s):  
Surabhi Pandey ◽  
B.K. Singh
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Inhibitory Activity ◽  
In Silico ◽  
Active Sites ◽  
De Novo ◽  
Docking Studies ◽  
Target Protein ◽  
Design And Development ◽  
Reference Drug

Background: There are over 44 million persons who suffer with Alzheimer’s disease (AD) worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy. Among all AChEIs donepezil possesses lowest adverse effects, it can treat mildmoderate- severe AD and only once-daily dosing is required. Therefore, donepezil is recognized as a significant prototype for design and development of new drug molecule. Methods: In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. Results: As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by insilico study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, - 8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity of - 6.32 kcal/mol. Conclusion: Computer aided drug design approach has been playing an important role in the design and development of novel anti- AD drugs. With the help of structure based drug design some novel analogues of donepezil have been designed and the molecular docking studies with structure based ADME properties prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed compounds with target protein i.e. AChE has been evaluated and the resulting data from docking studies explains that all of the newly designed analogues had significantly high affinity towards target protein compared to donepezil as a reference ligand.

scholarly journals In Vitro and In Silico Approaches for the Antileishmanial Activity Evaluations of Actinomycins Isolated from Novel Streptomyces smyrnaeus Strain UKAQ_23

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 887
Author(s):  
Kamal A. Qureshi ◽  
Ibrahim Al Nasr ◽  
Waleed S. Koko ◽  
Tariq A. Khan ◽  
M. Qaiser Fatmi ◽  
...  
Keyword(s):  
In Silico ◽  
Leishmania Major ◽  
Actinomycin D ◽  
Leishmania Species ◽  
Binding Pocket ◽  
Docking Studies ◽  
Antileishmanial Activity ◽  
Target Protein ◽  
Lutzomyia Longipalpis

Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis.

Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases

2009 ◽  
Vol 44 (9) ◽  
pp. 3703-3711 ◽  
Author(s):  
Aggeliki Politi ◽  
Serdar Durdagi ◽  
Panagiota Moutevelis-Minakakis ◽  
George Kokotos ◽  
Manthos G. Papadopoulos ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
In Silico ◽  
3D Qsar ◽  
Docking Studies ◽  
Renin Inhibitors ◽  
In Silico Docking

scholarly journals In silico screening of anti-inflammatory constituents with good drug-like properties from twigs of Cinnamomum cassia based on molecular docking and network pharmacology

2021 ◽  
Vol 18 (10) ◽  
pp. 2125-2131
Author(s):  
Qing Zhang ◽  
Ruolan Li ◽  
Jia Liu ◽  
Wei Peng ◽  
Yongxiang Gao ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Target Protein ◽  
Network Pharmacology ◽  
Active Constituent ◽  
In Silico Screening ◽  
Active Compounds ◽  
Target Proteins ◽  
Cinnamomum Cassia ◽  
Anti Inflammatory

Purpose: To investigate by in silico screening the anti-inflammatory constituents of Cinnamomum cassia twigs. Methods: Information on the constituents of C. cassia twigs was retrieved from the online Traditional Chinese Medicines (TCM) database and literature. Inflammation-related target proteins were identified from DrugBank, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), Genetic Association Database (GAD), and PharmGKB. The identified compounds were filtered by Lipinski’s rules with Discovery Studio software. The “Libdock” module was used to perform molecular docking; LibdockScores and default cutoff values for hydrogen bonds and van der Waals interactions were recorded. LibdockScores between the prototype ligand and target protein were set as the threshold; compounds with higher LibdockScores than threshold were regarded as active compounds. Cytoscape software was used to construct active constituent-target protein interaction networks. Results: Sixty-nine potential inflammatory constituents with good drug-like properties in C. cassia twigs were screened in silico based on molecular docking and network pharmacology analysis. JAK2, mPEGS-1, COX-2, IL-1β, and PPARγ were considered the five most important target proteins. Compounds such as methyl dihydromelilotoside, hierochin B, dihydromelilotoside, dehydrodiconiferyl alcohol, balanophonin, phenethyl (E)-3-[4-methoxyphenyl]-2-propenoate, quercetin, and luteolin each interacted with more than six of the selected target proteins. Conclusion: C. cassia twigs possess active compounds with good drug-like properties that can potentially be developed to treat inflammation with multi-components on multi-targets.

scholarly journals In silico screening of known small molecules to bind ACE2 specific RBD on Spike Glycoprotein of SARS-CoV-2 for repurposing against COVID-19

2020 ◽  
Author(s):  
Bharath B R ◽  
Hrishikesh Damle ◽  
Shiban Ganju ◽  
LathaDamle
Keyword(s):  
Small Molecules ◽  
In Silico ◽  
Md Simulation ◽  
Drug Repurposing ◽  
Cell Receptor ◽  
Docking Studies ◽  
Receptor Interaction ◽  
Spike Glycoprotein ◽  
In Silico Screening ◽  
Novel Drugs

Abstract Human coronavirus (SARS-CoV-2) is causing a pandemic with significant morbidity and mortality. Although, no effective novel drugs are available, drug repurposing is emerging as an effective strategy. In this study, we present an in silico drug repurposing study implementing successful concepts of computer aided drug design (CADD) technology with an objective to repurpose known drugs to interfere the viral cellular entry via the spike glycoprotein (SARS-CoV-2-S), which mediates the virus–cell receptor interaction. SARS-CoV-2-S uses ACE2 to enter cells. Totally, 4015 known and approved small molecules were screened for interaction with SARS-CoV-2 S through docking studies and 15 lead molecules were shortlisted. Further, three molecules streptomycin, ciprofloxacin and Glycyrrhizic acid (GA) were selected based on their reported anti-viral activity, safety, availability, affordability and subjected for Molecular Dynamics (MD) simulation. The MD simulation results indicate that GA from plant origin may be repurposed against SARS-CoV-2 and further studies are needed for validation.

Sign in / Sign up

Export Citation Format

Share Document