scholarly journals Identification of a putative anti-rheumatoid arthritis molecule by virtual screening

2020 ◽  
Vol 19 (6) ◽  
pp. 1255-1261
Author(s):  
Shazi Shakil ◽  
Adel M Abuzenadah ◽  
Suzan M. Attar ◽  
Omar Fathaldin ◽  
Rajaa Al-Raddadi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Free Energy ◽  
Virtual Screening ◽  
Thymidylate Synthase ◽  
Molecular Descriptors ◽  
Amino Acid Residues ◽  
Methotrexate Interaction ◽  
Inhibitor Design ◽  
Interaction Site ◽  
Free Energy Of Binding

Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis. Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check. Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions. Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation. Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screening

scholarly journals An Infrastructure to Mine Molecular Descriptors for Ligand Selection on Virtual Screening

2014 ◽  
Vol 2014 ◽  
pp. 1-9
Author(s):  
Vinicius Rosa Seus ◽  
Giovanni Xavier Perazzo ◽  
Ana T. Winck ◽  
Adriano V. Werhli ◽  
Karina S. Machado
Keyword(s):  
Virtual Screening ◽  
Molecular Descriptors ◽  
Protein A ◽  
Daily Basis ◽  
Rational Drug Design ◽  
Ligand Interaction ◽  
Zinc Database ◽  
Rational Drug ◽  
Tree Models ◽  
Free Energy Of Binding

The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data warehouse-based infrastructure to mine molecular descriptors for virtual screening (VS). We performed experiments that consider as target the receptor HIV-1 protease and different compounds for this protein. A set of 9 molecular descriptors are taken as the predictive attributes and the free energy of binding is taken as a target attribute. By applying the J48 algorithm over the data we obtain decision tree models that achieved up to 84% of accuracy. The models indicate which molecular descriptors and their respective values are relevant to influence good FEB results. Using their rules we performed ligand selection on ZINC database. Our results show important reduction in ligands selection to be applied in VS experiments; for instance, the best selection model picked only 0.21% of the total amount of drug-like ligands.

scholarly journals NUMBER OF RUNS VARIATIONS ON AUTODOCK 4 DO NOT HAVE A SIGNIFICANT EFFECT ON RMSD FROM DOCKING RESULTS

2021 ◽  
Vol 8 (6) ◽  
pp. 476-480
Author(s):  
M.R.F. Pratama ◽  
S. Siswandono
Keyword(s):  
Free Energy ◽  
Estrogen Receptor ◽  
Amino Acid ◽  
Hydrogen Bonds ◽  
Linear Equation ◽  
Significant Contribution ◽  
Amino Acid Residues ◽  
Maximum Difference ◽  
Binding Inhibition ◽  
Free Energy Of Binding

The aim. The number of runs in the docking process with AutoDock 4 is known to play an important role in the validity of the results obtained. The greater the number of runs it is often associated with the more valid docking results. However, it is not known exactly how the most ideal runs in the docking process with AutoDock 4. This study aims to determine the effect of the number of runs docking processes with AutoDock 4 on the validity of the docking results.Materials and methods. The method used is the redocking process with AutoDock 4.2.6. The receptor used is an estrogen receptor with ligand reference estradiol (PDB ID 1GWR). Variations were made on the number of runs from 10 to 100 in multiples of 10. The parameters observed were RMSD, free energy of binding, inhibition constants, amino acid residues, and the number of hydrogen bonds.Results. All experiments produce identical bond free energy, where the maximum difference in inhibition constant is only 0.06 nM. The lowest RMSD is indicated by the number of runs of 60, with a RMSD value of 0.942. There is no linear relationship between the number of runs and RMSD, with R in the linear equation of 0.4607.Conclusion. Overall, the number of runs does not show a significant contribution to the validity of the results of docking with AutoDock 4. However, these results have only been proven with the receptors used.

scholarly journals CHEMICAL STRUCTURE OPTIMIZATION OF LUPEOL AS ER-Α AND HER2 INHIBITOR

2018 ◽  
Vol 11 (6) ◽  
pp. 298 ◽  
Author(s):  
Mohammad Rizki Fadhil Pratama ◽  
Sutomo S
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Chemical Structure ◽  
Structure Optimization ◽  
Basis Set ◽  
Amino Acid Residues ◽  
Her2 Positive ◽  
Hartree Fock ◽  
Anticancer Properties ◽  
Free Energy Of Binding

Objectives: Lupeol, a triterpenoid isolated from Kasturi (Mangifera casturi) fruit has been known for having several pharmacological activities, including anticancer properties. Lupeol showed antiproliferative activity toward many cancer cells line including breast cancer. Lupeol showed promising potency as both ER-α and HER2 inhibitors, although still lower than known ER-α and HER2 Inhibitors. Chemical structure optimization of lupeol was predicted could increase the affinity of lupeol derivatives against ER-α and HER2. This study aims to determine lupeol derivative with the highest affinity against ER-α and HER2.Methods: All ligands were sketched and optimized using Gaussian 03W with Hartree–Fock method basis set 3-21G. Molecular docking was performed using Autodock 4.2.6 on several modified chemical structure of lupeol against active site of ER-α and HER2. The main parameter used was the free energy of binding and inhibition constants as affinity marker.Results: The docking results show that lupeol derivative with an amine group (Lupeol-2) and ethyl group (Lupeol-4) at position C3 provide the highest affinity with the free energy of binding and dissociation constant −12.24 kcal/mol and 1.07 nM for ER-α also −9.63 kcal/mol and 86.94 nM for HER2, respectively. Interestingly, although lupeol derivatives showed higher affinity toward ER-α, their amino acid residues were closer to the interaction on HER2.Conclusion: These results predict that lupeol have greater potential to be developed as a HER2 inhibitor. Further, derivate lupeol-4 should be potential to be developed as HER2-positive breast cancer therapy.

scholarly journals Virtual Screening Kandungan Senyawa Kipas Laut (Gorgonia mariae) sebagai Anti-Asma

2020 ◽  
Vol 16 (2) ◽  
pp. 199
Author(s):  
Faruk Jayanto Kelutur ◽  
Resmi Mustarichie ◽  
Abdul Kakhar Umar
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
In Silico ◽  
Log P ◽  
P Value ◽  
Amino Acid Residues ◽  
Test Compound ◽  
Discovery Studio ◽  
The People ◽  
Pharmacological Targets

<p>Kipas laut (<em>Gorgonia mariae</em>) telah digunakan masyarakat Maluku secara turun temurun sebagai obat asma. Kandungan metabolit sekunder yang paling dominan dalam kipas laut adalah sterol, dimana memiliki aktivitas terapi melalui efek sinergisme antara senyawa metabolit dengan polivalent activity. Pengujian kipas laut sebagai anti-asma belum pernah dilaporkan sebelumnya. Oleh karena itu, perlu dilakukan virtual screening menggunakan metode in silico pada komponen sterol kipas laut sebagai tahap awal dalam menentukan efektivitas terapi anti-asma dengan memprediksi nilai ikatan energi bebas (ΔG), konstanta inhibisi (Ki), dan interaksi residu asam amino menggunakan Autodock Tools 4.2 dan Discovery Studio 2016 Client®. Keamanan dan efektivitas kandidat obat dievaluasi menggunakan parameter dari Lipinski Rule of Five dan pre-ADMET. Hasil penelitian menunjukkan bahwa konstanta inhibisi dan ikatan energi bebas (Ki; ΔG) dari komponen senyawa kipas laut dapat diurutkan secara potensial yaitu 4,24-dimetil kolestanol  (0,809; -12,40) &gt; 24-metil-22-dehidrokolesterol (0,864; -12,36) &gt; 23-demetil gorgosterol (1,74; -11,95) &gt; 4,24-dimetil-22-dehidrokolestanol (1,89; -11,90). Residu asam amino yang berperan penting dalam aktivitas inhibisi hCHIT1 adalah 213-ASP. Semua komponen senyawa uji memiliki nilai log P lebih dari 5 yang menunjukkan bahwa kelarutan dan toksisitas perlu diperhatikan. Evaluasi distribusi pre-ADMET berdasarkan nilai dari pengikatan protein plasma menunjukan bahwa senyawa uji dapat berdifusi menembus membran plasma dan berinteraksi sesuai target farmakologi. Selain itu, hasil parameter uji toksisitas menunjukkan bahwa senyawa 23-demetil gorgosterol dan 4,24-dimetil-22-dehidrokolestanol memiliki potensi sebagai anti-asma.</p><p><strong>Virtual Screening of the Compounds in Gorgonians </strong><strong>(<em>Gorgonia mariae</em>) as anti-asthma. </strong>The people of Maluku have used Kipas laut (G. mariae) for generations as an asthma medicine. The secondary metabolite that is most dominant in kipas laut is sterols, which have therapeutic activity through the synergistic effect between metabolite compounds and polyvalent activity. Anti-asthma activity of kipas laut has never been reported. Therefore, it is necessary to do virtual screening using the in silico method on the sterol component of kipas laut as a first step in determining the effectiveness of anti-asthma therapy by predicting the value of free energy bonds (ΔG), constant inhibition (K<sub>i</sub>), and interactions of amino acid residues using Autodock Tools 4.2 and Discovery Studio 2016 Client®. The effectiveness and safety of prospective drugs are evaluated using the Lipinski Rule of Five and pre-ADMET. The results showed that the value of inhibition constants and free energy bonds (Ki; ΔG) on the compound of kipas laut that was potentially sorted was 4.24-dimethyl cholestanol (0.809; -12.40) &gt; 24-methyl-22-dehydrocholesterol (0.864; -12.36) &gt; 23-demethyl gorgosterol (1.74; -11.95) &gt; 4.24-dimethyl-22-dehidrokolestanol (1.89; -11.90). The crucial residues of amino acids is 213-ASP, which play a significant role in hCHIT1 inhibitory activity. All components of the test compound have a log P value of more than five, which indicates that solubility and toxicity need to be considered. Evaluation of the pre-ADMET based on the value of plasma protein binding shows that the test compound can diffuse through the plasma membrane and interact according to pharmacological targets. In addition, the results of the toxicity test showed that 23-demethyl gorgosterol and 4.24-dimethyl-22-dehidrokolestanol compounds have potential as anti-asthma.</p>

scholarly journals Virtual Screening Kandungan Senyawa Kipas Laut (Gorgonia mariae) sebagai Anti-Asma

2020 ◽  
Vol 16 (2) ◽  
pp. 48
Author(s):  
Faruk Jayanto Kelutur ◽  
Resmi Mustarichie ◽  
Abdul Kakhar Umar
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
In Silico ◽  
Log P ◽  
P Value ◽  
Amino Acid Residues ◽  
Test Compound ◽  
Discovery Studio ◽  
The People ◽  
Pharmacological Targets

<p><strong>ABSTRAK.</strong> Kipas laut (<em>Gorgonia mariae</em>) telah digunakan masyarakat Maluku secara turun temurun sebagai obat asma. Kandungan metabolit sekunder yang paling dominan dalam kipas laut adalah sterol, dimana memiliki aktivitas terapi melalui efek sinergisme antara senyawa metabolit dengan polivalent activity. Pengujian kipas laut sebagai anti-asma belum pernah dilaporkan sebelumnya. Oleh karena itu, perlu dilakukan virtual screening menggunakan metode in silico pada komponen sterol kipas laut sebagai tahap awal dalam menentukan efektivitas terapi anti-asma dengan memprediksi nilai ikatan energi bebas (ΔG), konstanta inhibisi (Ki), dan interaksi residu asam amino menggunakan Autodock Tools 4.2 dan Discovery Studio 2016 Client®. Keamanan dan efektivitas kandidat obat dievaluasi menggunakan parameter dari Lipinski Rule of Five dan pre-ADMET. Hasil penelitian menunjukkan bahwa konstanta inhibisi dan ikatan energi bebas (Ki; ΔG) dari komponen senyawa kipas laut dapat diurutkan secara potensial yaitu 4,24-dimetil kolestanol  (0,809; -12,40) &gt; 24-metil-22-dehidrokolesterol (0,864; -12,36) &gt; 23-demetil gorgosterol (1,74; -11,95) &gt; 4,24-dimetil-22-dehidrokolestanol (1,89; -11,90). Residu asam amino yang berperan penting dalam aktivitas inhibisi hCHIT1 adalah 213-ASP. Semua komponen senyawa uji memiliki nilai log P lebih dari 5 yang menunjukkan bahwa kelarutan dan toksisitas perlu diperhatikan. Evaluasi distribusi pre-ADMET berdasarkan nilai dari pengikatan protein plasma menunjukan bahwa senyawa uji dapat berdifusi menembus membran plasma dan berinteraksi sesuai target farmakologi. Selain itu, hasil parameter uji toksisitas menunjukkan bahwa senyawa 23-demetil gorgosterol dan 4,24-dimetil-22-dehidrokolestanol memiliki potensi sebagai anti-asma.</p><p><strong>ABSTRACT. Virtual Screening of the Compounds in Gorgonians </strong><strong>(<em>Gorgonia mariae</em>) as anti-asthma. </strong>The people of Maluku have used Kipas laut (G. mariae) for generations as an asthma medicine. The secondary metabolite that is most dominant in kipas laut is sterols, which have therapeutic activity through the synergistic effect between metabolite compounds and polyvalent activity. Anti-asthma activity of kipas laut has never been reported. Therefore, it is necessary to do virtual screening using the in silico method on the sterol component of kipas laut as a first step in determining the effectiveness of anti-asthma therapy by predicting the value of free energy bonds (ΔG), constant inhibition (K<sub>i</sub>), and interactions of amino acid residues using Autodock Tools 4.2 and Discovery Studio 2016 Client®. The effectiveness and safety of prospective drugs are evaluated using the Lipinski Rule of Five and pre-ADMET. The results showed that the value of inhibition constants and free energy bonds (Ki; ΔG) on the compound of kipas laut that was potentially sorted was 4.24-dimethyl cholestanol (0.809; -12.40) &gt; 24-methyl-22-dehydrocholesterol (0.864; -12.36) &gt; 23-demethyl gorgosterol (1.74; -11.95) &gt; 4.24-dimethyl-22-dehidrokolestanol (1.89; -11.90). The crucial residues of amino acids is 213-ASP, which play a significant role in hCHIT1 inhibitory activity. All components of the test compound have a log P value of more than five, which indicates that solubility and toxicity need to be considered. Evaluation of the pre-ADMET based on the value of plasma protein binding shows that the test compound can diffuse through the plasma membrane and interact according to pharmacological targets. In addition, the results of the toxicity test showed that 23-demethyl gorgosterol and 4.24-dimethyl-22-dehidrokolestanol compounds have potential as anti-asthma.</p>

scholarly journals Discovery of New Classes of Glycine transporter 2 (GlyT2) Inhibitors and Study of GlyT2 Selectivity by Combination of Novel Structural Based Virtual Screening Approach and Free Energy Perturbation (FEP+) Calculations

2019 ◽  
Author(s):  
Filip Fratev ◽  
Manuel Miranda-Arango ◽  
Elvia Padilla ◽  
Suman Sirimulla
Keyword(s):  
Chronic Pain ◽  
Free Energy ◽  
Amino Acid ◽  
Virtual Screening ◽  
Basic Amino Acid ◽  
Free Energy Perturbation ◽  
Amino Acid Residues ◽  
Strong Inhibitor ◽  
Energy Perturbation

In recent years, the mammalian GlyT2 transporter have emerged as a promising target for the development of anti-chronic pain agents. In our current work, we discovered a new set of promising hits that inhibit the glycine transport at nano and micromolar activity and have excellent selectivity over GlyT1 (as shown by in vitro studies), using a newly designed virtual screening (VS) protocol that combines a structure-based pharmacophore and docking screens. Furthermore, the free energy perturbation (FEP+ protocol) calculations and molecular dynamics (MD) studies revealed the GlyT2 amino acid residues critical for the binding and selectivity of both Glycine and our Lead1 compound. The FEP+ results well-matched available literature mutational data proving the quality of generated GlyT2 structure. Based on these calculations we propose that Lead1 may also be a strong inhibitor of the neutral and basic amino acid transporter B (0+) (SLC6A14). Thus, the subsequent lead optimization and characterization of refined compounds may lead to both chronic pain and pancreatic cancer agents addressing an unmet and challenging clinical needs.

Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A

2017 ◽  
Vol 14 (10) ◽  
pp. 1122-1137 ◽  
Author(s):  
Nivedita Singh ◽  
Parameswaran Saravanan ◽  
M.S. Thakur ◽  
Sanjukta Patra
Keyword(s):  
Free Energy ◽  
Active Site ◽  
Signal Transduction Pathway ◽  
Docking Study ◽  
Primary Objective ◽  
Cgmp Level ◽  
Active Site Residues ◽  
Aromatic Fragment ◽  
Docking Approach ◽  
Free Energy Of Binding

Background: Phosphodiesterases 9A (PDE9A) is one of the prominent regulating enzymes of the signal transduction pathway having highest catalytic affinity for second messenger, cGMP. When the cGMP level is lowered, an uncontrolled expression of PDE9A may lead to various neurodegenerative diseases. To regulate the catalytic activity of PDE9A, potent inhibitors are needed. Objective: The primary objective of the present study was to develop new xanthine based inhibitors targeting PDE9A. This study was an attempt to bring structural diversification in PDE9A inhibitor development because most of the existing inhibitors are constructed over pyrazolopyrimidinone scaffold. Methods: Manual designing and parallel molecular docking approach were used for the development of xanthine derivatives. In this study, N1, N3, N9 and C8 positions of xanthine scaffold were selected as substitution sites to design 200 new compounds. Reverse docking and pharmaceutical analyses were used for final validation of most promising compounds. Results: By keeping free energy of binding cut-off of -6.0 kcal/mol, 52 compounds were screened. The compounds with substitution at N1, N3 and C8 positions of xanthine showed good occupancy in PDE9A active site pocket with a significant interaction pattern. This was further validated by screening different factors such as free energy of binding, inhibition constant and interacting active site residues in the 5Å region. Substitution at C8 position with phenyl substituent determined the inhibition affinity of compounds towards PDE9A by establishing a strong hydrophobic - hydrophobic interaction. The alkyl chain at N1 position generated selectivity of compounds towards PDE9A. The aromatic fragment at N3 position increased the binding affinity of compounds. Thus, by comparative docking study, it was found that compound 39-42 formed selective interaction towards PDE9A over other members of the PDE superfamily. Conclusion: From the present study, N1, N3 and C8 positions of xanthine were concluded as the best sites for substitution for the generation of potent PDE9A inhibitors.

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