scholarly journals Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sabitu Babatunde Olasupo ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Binding Affinity ◽  
Dopamine Transporter ◽  
Hydrophobic Interactions ◽  
Docking Simulation ◽  
Experimental Investigations ◽  
Template Molecule ◽  
Molecular Docking Simulation ◽  
Drug Candidates

Abstract Background The inhibition of dopamine transporter is known to play a significant role in the treatment of schizophrenia-related and other mental disorders. In a continuing from our previous study, computational drug design approach, molecular docking simulation, and pharmacokinetics study were explored for the identification of novel inhibitors dopamine transporter as potential Antischizophrenic agents. Consequently, thirteen (13) new inhibitors of dopamine transporter were designed by selecting the molecule with serial number 39 from our previous study as the template molecule because  it exhibits good pharmacological attributes. Results Molecular docking simulation results revealed excellent molecular interactions between the protein target (PDB: 4m48) and the ligands (designed inhibitors) with major interactions that involved hydrogen bonding and hydrophobic interactions. Also, some of the designed inhibitors displayed a superior binding affinity range from − 10.0 to − 10.7 kcal/mol compared to the referenced drug (Lumateperone) with a binding affinity of − 9.7 kcal/mol. Computed physicochemical parameters showed that none of the designed inhibitors including the referenced drug violate Lipinski’s rule of five indicating that all the designed inhibitors would be orally bioavailable as potential drug candidates. Similarly, the ADMET/pharmacokinetics evaluations of some designed inhibitors revealed that they possessed good absorption, distribution, metabolism and excretion properties and none of the inhibitors is neither carcinogens nor toxic toward human ether-a-go-go related gene (hERG I) inhibitor or skin sensitization. Likewise, the BOILED-Egg graphics unveils that all the designed inhibitors demonstrate a high probability to be absorbed by the human gastrointestinal tract and could permeate into the brain. Besides, the predicted bioactive parameters suggested that all the selected inhibitors would be active as drug candidates. Furthermore, the synthetic accessibility scores for all the selected inhibitors and referenced drug lied within the easy zone (i.e., between 1–4) with their computed values range from 2.55 to 3.92, this implies that all the selected inhibitors would be very easy to synthesize in the laboratory. Conclusions Hence, all the designed inhibitors having shown excellent pharmacokinetics properties and good bioavailabilities attributes with remarkable biochemical interactions could be developed and optimized as novel Antischizophrenic agents after the conclusion of other experimental investigations.

scholarly journals in silico Anti-Cholinestarase Activity of Flavonoids: A Computational Approach

2019 ◽  
Vol 31 (12) ◽  
pp. 2859-2864
Author(s):  
Niraj Kumar Singh ◽  
Somdutt Mujwar ◽  
Debapriya Garabadu
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Simulation ◽  
Docking Studies ◽  
Computational Approach ◽  
Molecular Docking Simulation ◽  
Flavonoid Compounds ◽  
Potent Inhibition ◽  
Potential Binding ◽  
Derivatives Of

In the present study, a computational approach has been designed to evaluate the potential anti-cholinesterase activity of derivatives of flavonoids. Molecular docking studies is performed for the 9 flavonoids against the human acetylcholine (ACh) enzyme to evaluate their binding affinity for having anti-alzheimer activity. All the 9 flavonoid compounds exhibited strong binding affinity that promises potent inhibition of human acetylcholine enzyme. Potential binding affinity of all the flavonoids against human acetylcholine enzyme confirms their possible mechanism of action by using AutoDock based molecular docking simulation technique. Thus, these flavonoid compounds could be presumed to be potential anti-cholinesterase drugs.

Discovery of Natural Product Compounds as Dengue Virus NS5 Methyltransferase Inhibitor Candidate through in Silico Method

2020 ◽  
Vol 840 ◽  
pp. 270-276
Author(s):  
Anjas Randy Bagastama ◽  
Ahmad Husein Alkaff ◽  
Usman Sumo Friend Tambunan
Keyword(s):  
Molecular Docking ◽  
Dengue Virus ◽  
Natural Product ◽  
In Silico ◽  
Antiviral Agents ◽  
Docking Simulation ◽  
Simulation Method ◽  
Molecular Docking Simulation ◽  
Drug Candidates ◽  
Natural Product Compounds

Dengue is a global health problem which predominantly affected the tropical and subtropical region of Asia, Africa, and America. However, there are no available antiviral agents to treat dengue virus (DENV) infection. This study was conducted to utilize natural product compounds as an inhibitor of NS5 Methyltransferase, a viral protein which plays an essential role in the synthesis of DENV RNA. The natural product compounds were collected from the Universal Natural Product Database (UNPD), totaling 229,000 compounds. The in silico screening of the natural product compounds was performed by molecular docking simulation method, which simulates the interaction of the compounds on the active site of the NS5 methyltransferase. From the molecular docking simulation, about 51 compounds showed better affinity and interaction compared to the standard compound, S-Adenosyl-L-Homocysteine (SAH). Then, a series of pharmacological tests were performed to find the best drug candidates by employing DataWarrior and SwissADME software. Finally, three natural product compounds, namely UNPD98966, UNPD183023, and UNDP104952, were regarded as the best inhibitor against NS5 methyltransferase based on its molecular affinity and interaction. These compounds also showed potential as drug candidates due to their desirable pharmacological properties.

Synthesis of 1,3,4-oxadiazoles as promising anticoagulant agents

RSC Advances ◽  
2016 ◽  
Vol 6 (29) ◽  
pp. 24797-24807 ◽  
Author(s):  
Vishwanathan B. Iyer ◽  
Gurupadayya B. M. ◽  
Bharathkumar Inturi ◽  
Venkata Sairam K. ◽  
Gurubasavaraj V. Pujar
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Vitamin K ◽  
Factor Xa ◽  
Docking Simulation ◽  
Molecular Docking Simulation ◽  
Vitamin K Epoxide Reductase ◽  
Target Proteins ◽  
Anticoagulant Agents ◽  
Epoxide Reductase

A series of 1,3,4-oxadiazoles were designed and subjected to molecular docking simulation onto the enzymes vitamin K epoxide reductase (PDB: 3KP9) and factor Xa (PDB: 1NFY) to visualize their binding affinity towards the said target proteins.

scholarly journals Homology modeling and molecular docking simulation of some novel imidazo[1,2-a]pyridine-3-carboxamide (IPA) series as inhibitors of Mycobacterium tuberculosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mustapha Abdullahi ◽  
Shola Elijah Adeniji ◽  
David Ebuka Arthur ◽  
Abdurrashid Haruna
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Homology Modeling ◽  
Binding Affinity ◽  
Docking Simulation ◽  
Computational Method ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Standard Drug ◽  
Molecular Docking Simulation

Abstract Background Tuberculosis (TB) remains a serious global health challenge that is caused by Mycobacterium tuberculosis and has killed numerous people. This necessitated the urgent need for the hunt and development of more potent drugs against the fast-emerging extensively drug-resistant (XDR) and multiple-drug-resistant (MDR) M. tuberculosis strains. Mycobacterium tuberculosis cytochrome b subunit of the cytochrome bc1 complex (QcrB) was recognized as a potential drug target in M. tuberculosis (25618/H37Rv) for imidazo[1,2-a]pyridine-3-carboxamides whose crystal strucuture is not yet reported in the Protein Data Bank (PDB). The concept of homology modeling as a powerful and useful computational method can be applied, since the M. tuberculosis QcrB protein sequence data are available. Results The homology model of QcrB protein in M. tuberculosis was built from the X-ray structure of QcrB in M. smegmatis as a template using the Swiss-Model online workspace. The modeled protein was assessed, validated, and prepared for the molecular docking simulation of 35 ligands of N-(2-phenoxy)ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to analyze their theoretical binding affinities and modes. The docking results showed that the binding affinity values ranged from − 6.5 to − 10.1 kcal/mol which confirms their resilience potency when compared with 6.0kcal/mol of isoniazid standard drug. However, ligands 2, 7, 22, 26, and 35 scored higher binding affinity values of − 9.60, − 9.80, − 10.10, − 10.00, and − 10.00 kcal/mol, and are respectively considered as the best ligands among others with better binding modes in the active site of the modeled QcrB protein. Conclusion The information derived in this research revealed some potential hits and paved a route for structure-based drug discovery of new hypothetical imidazo pyridine amide analogs as anti-tubercular drug candidates.

Design, Molecular docking, Synthesis and Biological evaluation of 5, 7 dimethyl pyrido(2, 3-d)pyrimidin-4-one and 4,5 dihydro pyrazolo (3, 4-d) pyrimidines for cytotoxic activity

2021 ◽  
pp. 3029-3038
Author(s):  
M. Sathish Kumar ◽  
M. Vijey Aanandhi
Keyword(s):  
Molecular Docking ◽  
Docking Simulation ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hep G2 ◽  
Molecular Docking Simulation ◽  
Hela Cell Lines ◽  
Benzene Diazonium ◽  
Synthesis And Biological Evaluation ◽  
Mcf 7

The fused pyrimidine derivatives are potent tyrosine kinase and thymidylate synthase inhibitors. The compound 3-(4-sulphonyl amino)-2-methyl thio-6-phenyl azo-5, 7-dimethyl pyrido(2,3-d)pyrimidin-4-one was synthesized from Ethyl 2-amino-4,6-dimethylpyridine-3-carboxylate, benzene diazonium chloride, benzene sulphonyl amino isothiocyanate in subsequent reactions. 1-(1, 3-benzothiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidines were synthesized from 1, 3-benzothiazole, 2-thiol, Hydrazine Hydrate, 2-hydrazinyl-1, 3-benzothiazole and aldehydes in subsequent reactions. Twenty-five derivatives pyrimidine scaffolds were designed and performed molecular docking studies for the ability to inhibit the target protein using molecular docking simulation, selective compounds were synthesized and characterized by spectral methods. All the synthesized compounds evaluated for their antioxidant activity and MTT assay exhibited compounds 13c, 13e and 14d can be potential anticancer candidates against MCF-7, Hep G2 and Hela cell lines respectively. Based on all the studies conclude that good agreement was observed between the top-ranked docking scores and top experimental inhibitors when compared with standards ascorbic acid and imatinib. Hence, the compounds could be considered as new anticancer hits for further lead optimization.

Binding Investigation of Integrin αvβ3 With Its Inhibitors by SPR Technology and Molecular Docking Simulation

2010 ◽  
Vol 15 (2) ◽  
pp. 131-137 ◽  
Author(s):  
Yaqin Liu ◽  
Yuanjiang Pan ◽  
Yuhong Xu
Keyword(s):  
Molecular Docking ◽  
Binding Sites ◽  
Structural Model ◽  
Docking Simulation ◽  
Integrin Αvβ3 ◽  
Equilibrium Dissociation Constant ◽  
Molecular Docking Simulation ◽  
Spr Biosensor ◽  
Inhibitor Discovery ◽  
Equilibrium Dissociation

Integrins play critical roles in the process of angiogenesis and are attractive targets for anticancer therapies. It is desirable to develop new types of small-molecule inhibitors of integrin. Herein, the binding features of several inhibitors to integrin αvβ3 have been studied by surface plasmon resonance (SPR) biosensor technology and molecular docking analyses. The SPR results indicated that the equilibrium dissociation constant (KD) values are evaluated for the inhibitors and showed that the KD value of cyclopeptide c-Lys is much lower than the reference molecule. In addition, the 3D structural model of integrin αvβ3 was generated according to the crystal structure of the integrin αvβ3 complex, and the molecular docking simulation analyses revealed that the predicted binding sites for the most active cyclopeptide c-Lys were consistent with the reported structure. These results thus implied that cyclopeptide c-Lys could be developed as a novel inhibitor for integrin αvβ3. The current work has potential for application in structure-based integrin αvβ3 inhibitor discovery.

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