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Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions [chapter]

Irina F. Sevrioukova, Thomas L. Poulos
2015 Advances in Experimental Medicine and Biology  
This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions.  ...  Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs.  ...  Acknowledgments Financial support from the National Institute of General Medical Sciences (Grant GM57353) and the California Center for Antiviral Drug Discovery is gratefully appreciated.  ... 
doi:10.1007/978-3-319-16009-2_3 pmid:26002732 pmcid:PMC4532289 fatcat:7ujdyyp3sfgwblvrl56bop3zou

Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

Zbigniew Dutkiewicz, Renata Mikstacka
2018 Bioinorganic Chemistry and Applications  
Moreover, the molecular modeling of proteins and ligand docking to their active sites provide an insight into the mechanism of enzyme action and enable us to predict the sites of drug metabolism.  ...  The review presents the current status of knowledge about the use of the computational approach in studies of ligand-enzyme interactions for CYP1s.  ...  Docking may be used to provide information about the conformation of a bioactive ligand and its position in the binding site.  ... 
doi:10.1155/2018/3924608 pmid:30147715 pmcid:PMC6083639 fatcat:5hdcm4kyo5bd5aqqdhkjy3hpgi

Identifying the alpha-glucosidase inhibitory potential of dietary phytochemicals against diabetes mellitus type 2 via molecular interactions and dynamics simulation

Mohd Adnan Kausar, SMA Shahid, Sadaf Anwar, M Kuddus, Mohammad Kalim Ahmad Khan, Amany Mohammed Khalifa, Fahmida Khatoon, Abdullah D. Alotaibi, Salman F. Alkhodairy, Mejdi Snoussi, Jamal M. Arif
2022 Cellular and Molecular Biology  
Molecular dynamics simulation of 10 ns duration, CYP450 site of metabolism identification, and prediction of activity spectra for substances depicted the bromelain as the most stable inhibitor compared  ...  alpha-glucosidase in comparison to the best-known inhibitor, acarbose (ΔG: -7.93 kcal/mol).  ...  Interest conflict The authors declare no conflict of interest.  ... 
doi:10.14715/cmb/2021.67.5.3 fatcat:gaaxewiqgzghnfvn4cuihprweu

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Outi M. H. Salo-Ahen, Ida Alanko, Rajendra Bhadane, Alexandre M. J. J. Bonvin, Rodrigo Vargas Honorato, Shakhawath Hossain, André H. Juffer, Aleksei Kabedev, Maija Lahtela-Kakkonen, Anders Støttrup Larsen, Eveline Lescrinier, Parthiban Marimuthu (+7 others)
2020 Processes  
In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate  ...  In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields  ...  Their other study on the conformational changes of the SIRT2 substrate and inhibitor binding sites revealed the dynamic role of Phe96 in binding the inhibitor in SIRT2 [81] .  ... 
doi:10.3390/pr9010071 fatcat:x6pcyzoxevbvhncirfrkqiuppq

In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

Neha Gupta, Saurav Kumar Choudhary, Neeta Bhagat, Muthusamy Karthikeyan, Archana Chaturvedi
2021 Molecules  
We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C.  ...  This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.  ...  Acknowledgments: We would like to acknowledge Ashok K. Chauhan, Founder President, Amity University Uttar Pradesh, Noida for providing the infrastructure and support.  ... 
doi:10.3390/molecules26144147 pmid:34299422 pmcid:PMC8305770 fatcat:wbpg7f6jifhjbo5qkilljmylu4

Computational Prediction of Potential Inhibitors of the Main Protease of SARS-CoV-2

Renata Abel, María Paredes Ramos, Qiaofeng Chen, Horacio Pérez-Sánchez, Flaminia Coluzzi, Monica Rocco, Paolo Marchetti, Cameron Mura, Maurizio Simmaco, Philip E. Bourne, Robert Preissner, Priyanka Banerjee
2020 Frontiers in Chemistry  
To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to  ...  Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn  ...  A conformational change then occurs, and the positions adopted by the ligand from 30 to 100 ns preclude contacts with binding-site residues.  ... 
doi:10.3389/fchem.2020.590263 pmid:33425850 pmcid:PMC7786237 fatcat:6c7dvwelxndr3dyn6tejww3hlm

Computational Methods in Drug Discovery

G. Sliwoski, S. Kothiwale, J. Meiler, E. W. Lowe
2013 Pharmacological Reviews  
Authorship Contributions Wrote or contributed to the writing of the manuscript: Sliwoski, Kothiwale, Meiler, Lowe.  ...  Desolvation of ligand and binding pocket, shifts in the ligand and protein conformational ensembles, and reordering of water molecules in the binding site all contribute to binding free energies.  ...  Structural insight of binding site allowed the investigators to apply ligands containing an N-(2adamantyl) amide moiety in a drug design program.  ... 
doi:10.1124/pr.112.007336 pmid:24381236 pmcid:PMC3880464 fatcat:4dzrdkspkjecnombnchznma2ny

Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

Mubashir Hassan, Saba Shahzadi, Sung Y. Seo, Hany Alashwal, Nazar Zaki, Ahmed A. Moustafa
2018 Frontiers in Computational Neuroscience  
The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD).  ...  The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively.  ...  In the future, a molecular dynamics simulation study may be used as good computational approach to study the interactions of Aβ40 and Aβ42 with model neuronal membranes.  ... 
doi:10.3389/fncom.2018.00034 pmid:29910719 pmcid:PMC5992503 fatcat:df3qd4z7fnhbrdvraspthdruhq

Molecular Basis of Metabolism-Mediated Conversion of PK11195 from an Antagonist to an Agonist of the Constitutive Androstane Receptor

Bryan Mackowiak, Linhao Li, Matthew A. Welch, Daochuan Li, Jace W. Jones, Scott Heyward, Maureen A. Kane, Peter W. Swaan, Hongbing Wang
2017 Molecular Pharmacology  
We show that although PK11195 antagonizes hCAR in HepG2 cells, it induces the expression of CYP2B6 and CYP3A4, targets of hCAR and the pregnane X receptor (PXR), in HPH, HepaRG, and PXR-knockout HepaRG  ...  Here, we investigated the effects of PK11195 on hCAR in metabolically competent human primary hepatocytes (HPH) and HepaRG cells.  ...  The LC-MS analysis of PK11195 metabolism was performed in the Mass Spectrometry Center at the University of Maryland School of Pharmacy.  ... 
doi:10.1124/mol.117.108621 pmid:28442602 pmcid:PMC5452073 fatcat:ndlbq7huhnfzngzo6tarcyy7vy

The 18th European Symposium on Quantitative Structure–Activity Relationships

Anna Tsantili-Kakoulidou, Dimitris K Agrafiotis
2011 Expert Opinion on Drug Discovery  
effective binding in the kinase.  ...  Furthermore, the conducted docking studies elucidated the possible alternative binding mode of the ligands into the ATP binding cleft and assigned their physicochemical and structural features which promote  ...  Several different binding modes were produced due to the conformational flexibility of the small ligands compared to the dimensions of the active site.  ... 
doi:10.1517/17460441.2011.560604 pmid:22646021 fatcat:tb4bhvtnpzahxm4xba7iw4afuy

Potential Therapeutic Candidates against Chlamydia pneumonia Discovered and Developed In Silico Using Core Proteomics and Molecular Docking and Simulation-Based Approaches

Roqayah H. Kadi, Khadijah A. Altammar, Mohamed M. Hassan, Abdullah F. Shater, Fayez M. Saleh, Hattan Gattan, Bassam M. Al-ahmadi, Qwait AlGabbani, Zuhair M. Mohammedsaleh
2022 International Journal of Environmental Research and Public Health  
Molecular docking experiments were also evaluated using molecular dynamics simulations and the widely used MM-GBSA and MM-PBSA binding free energy techniques.  ...  In the present study, an approach named subtractive proteomics was employed to the core proteomes of five strains of C. pneumonia using various bioinformatic tools, servers, and software.  ...  Acknowledgments: The authors extend their appreciation to Taif University for funding the current work by Taif University Researchers Supporting Project number (TURSP-2020/59), Taif University, Taif, Saudi  ... 
doi:10.3390/ijerph19127306 pmid:35742569 fatcat:h772mre4xvhndlg3powxpebwae

Identification of FDA Approved Drugs Against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp) and 3-chymotrypsin-like Protease (3CLpro), Drug Repurposing Approach

Zahra Molavi, Sara Razi, Seyed Amir Mirmotalebisohi, Amirjafar Adibi, Marzieh Sameni, Farshid Karami, Vahid Niazi, Zahra Niknam, Morteza Aliashrafi, Mohammad Taheri, Soudeh Ghafouri-Fard, Shabnam jeibouei (+4 others)
2021 Biomedicine and Pharmacotherapy  
Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib  ...  In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach.  ...  Acknowledgments The authors thank the Proteomics Research Center of Shahid Beheshti University of Medical Sciences for their support in conducting this work (NO. 22784).  ... 
doi:10.1016/j.biopha.2021.111544 fatcat:aky3xdqbczbg5l4tt76i6dm754

Tripeptides from Allium subhirsitum L. extracts: Pharmacokinetics properties, toxicity prediction and in silico study against SARS-CoV-2 enzymes and pro-inflammatory proteins

Mejdi Snoussi, Emira Noumi, Amor Mosbah, Alaeddine Redissi, Mohd Saeed, Munazzah Tasleem, Mousa Alreshidi, Mohd Adnan, Ayshah Al-Rashidi, Arif Jamal Siddiqui, Kaïss Aouadi, Vincenzo De Feo (+1 others)
2022 Cellular and Molecular Biology  
The obtained promising results showed that the peptides (Asn-Asn-Asn) possess the highest binding affinities of -8.4 kcal/mol against S protein, (His-Phe-Gln) of -9.8 kcal/mol and (Gln-His-Phe) of -9.7  ...  Since no available clinically antiviral drugs have been approved to eradicate COVID-19 as of the writing of this report, this study aimed to investigate bioactive short peptides from Allium subhirsutum  ...  Structure-based virtual screening is applied to identify the best binding conformation of the ligands within the receptor binding site.  ... 
doi:10.14715/cmb/2021.67.4.17 fatcat:sfiduqjuxvesvocbkmipawdiqy

Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2

Victor Moreira de Oliveira, Matheus Nunes da Rocha, Emanuel Paula Magalhães, Francisco Rogênio da Silva Mendes, Márcia Machado Marinho, Ramon Róseo Paula Pessoa Bezerra de Menezes, Tiago Lima Sampaio, Hélcio Silva dos Santos, Alice Maria Costa Martins, Emmanuel Silva Marinho
2021 Future Journal of Pharmaceutical Sciences  
inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption  ...  In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV  ...  Acknowledgements The authors thank FUNCAP, CAPES and CNPq for financial support and scholarship.  ... 
doi:10.1186/s43094-021-00334-z pmid:34514004 pmcid:PMC8419828 fatcat:no62b5m7rjandbtwhbddw4sbou

Investigation of Antidepressant Properties of Yohimbine by Employing Structure-Based Computational Assessments

Munazzah Tasleem, Abdulwahed Alrehaily, Tahani M. Almeleebia, Mohammad Y. Alshahrani, Irfan Ahmad, Mohammed Asiri, Nadiyah M. Alabdallah, Mohd Saeed
2021 Current Issues in Molecular Biology  
Additionally, the in silico mutational study was carried out to understand the increase in therapeutic efficiency using site-directed mutagenesis.  ...  Yohimbine was investigated in this study to determine its antidepressant activity using molecular docking and pharmacokinetic analyses.  ...  Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/cimb43030127 pmid:34889886 fatcat:uvkeviga4vgtjkqjdr52jnpiei
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