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Ensemble Docking in Drug Discovery

Rommie E. Amaro, Jerome Baudry, John Chodera, Özlem Demir, J. Andrew McCammon, Yinglong Miao, Jeremy C. Smith
2018 Biophysical Journal  
This approach is now well established in the field of early-stage drug discovery.  ...  Ensemble docking corresponds to the generation of an "ensemble" of drug target conformations in computational structure-based drug discovery, often obtained by using molecular dynamics simulation, that  ...  the ensemble of protein: ligand complexes than apo-structures that are rarely sampled.  ... 
doi:10.1016/j.bpj.2018.02.038 pmid:29606412 pmcid:PMC6129458 fatcat:6kyspe4scneenklkuotmzs7xhe

Structure-Based Drug Design [chapter]

Kunbin Qu, Natasja Brooijmans
2007 Computational Methods for Protein Structure Prediction and Modeling  
While a number of kinase inhibitors have been approved for use in the clinic, kinases as drug targets still form a significant challenge due to protein flexibility in the kinase catalytic domain and issues  ...  Conformations of the conserved DFG motif is well known to be crucial for selective binding of many kinase inhibitors-including the cancer drug imatinib.  ...  In real-life applications, however, ligands are docked against non-native conformations of the protein, i.e. the apo structure or a structure of a different protein-ligand complex.  ... 
doi:10.1007/978-0-387-68825-1_5 fatcat:4zqde52aczhnjipufly7b4hwzi

Exploring the role of receptor flexibility in structure-based drug discovery

Ferran Feixas, Steffen Lindert, William Sinko, J. Andrew McCammon
2014 Biophysical Chemistry  
In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular  ...  The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development.  ...  Acknowledgments The authors would like to thank the members of the McCammon group for fruitful discussions.  ... 
doi:10.1016/j.bpc.2013.10.007 pmid:24332165 pmcid:PMC4459653 fatcat:k5dm4dqyxvga7iqm7guybp5okm

Pocket-Based Drug Design: Exploring Pocket Space

Xiliang Zheng, LinFeng Gan, Erkang Wang, Jin Wang
2012 AAPS Journal  
Also, the pockets at the proteinprotein interfaces (PPI) have been considered to further explore the pocket space for drug discovery.  ...  In one of two cases, we also included some applications of pockets located at the dimer interfaces to emphasize the role of PPI in drug discovery.  ...  These diverse pockets of a protein are particularly useful for target-based drug discovery as the detection of these binding pockets is considered as a premise of structure-based drug design.  ... 
doi:10.1208/s12248-012-9426-6 pmid:23180158 pmcid:PMC3535113 fatcat:7y65lisiyjbklnbbajbl6xzy7q

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

Andras Szilagyi, Ruth Nussinov, Peter Csermely
2013 Current Topics in Medicinal Chemistry  
Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same protein.  ...  Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein  ...  This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.  ... 
doi:10.2174/1568026611313010007 pmid:23409766 fatcat:fncwsjbahrb73n5gj6iga4qyxe

In Silico Strategies in Tuberculosis Drug Discovery

Stephani Joy Y. Macalino, Junie B. Billones, Voltaire G. Organo, Maria Constancia O. Carrillo
2020 Molecules  
While there are available therapeutics for this infection, slow-acting drugs, poor patient compliance, drug toxicity, and drug resistance require the discovery of novel TB drugs.  ...  In this paper, we discuss the current TB treatment, emergence of drug resistance, and the effective application of computational tools to the different stages of TB drug discovery when combined with traditional  ...  of required treatment urgently necessitates the discovery and development of newer and effective drugs for TB.  ... 
doi:10.3390/molecules25030665 pmid:32033144 pmcid:PMC7037728 fatcat:wh2uu64av5dndjkb4bhsykgagm

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

Kenneth Hallenbeck, David Turner, Adam Renslo, Michelle Arkin
2016 Current Topics in Medicinal Chemistry  
Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation.  ...  Here, we review three applications of cysteine-modifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules  ...  Acknowledgments The authors thank the reviewers for insightful comments and suggestions, the National Science Foundation for a Predoctoral Fellowship (KKH) and Pfizer Inc. for postdoctoral support (DMT  ... 
doi:10.2174/1568026616666160719163839 pmid:27449257 pmcid:PMC5321175 fatcat:mqekca7dkzhnhjbv7phtubuqzi

In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors

Veronica Salmaso, Kenneth A. Jacobson
2020 Biomolecules  
Molecular modeling has contributed to drug discovery for purinergic GPCRs, including adenosine receptors (ARs) and P2Y receptors (P2YRs).  ...  Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery.  ...  This has implications in the drug discovery field, offering, for example, the possibility to rationally develop allosteric modulators or ligands focusing on optimized kinetics together with thermodynamic  ... 
doi:10.3390/biom10060812 pmid:32466404 pmcid:PMC7356333 fatcat:jetcjvehljhobddu6mpwpa5f3y

Machine Learning Prediction of Allosteric Drug Activity from Molecular Dynamics

Filippo Marchetti, Elisabetta Moroni, Alessandro Pandini, Giorgio Colombo
2021 Journal of Physical Chemistry Letters  
In this context, it is common practice to use high-throughput screening for the discovery of non-natural allosteric drugs.  ...  typical of allosteric proteins.  ...  The extraordinary complexity of biochemical networks in healthy and disease conditions 3, 4 and the costs associated with drug discovery are however hampering the advent of this new era of therapeutics  ... 
doi:10.1021/acs.jpclett.1c00045 pmid:33843228 pmcid:PMC8154828 fatcat:r3znlmp7u5hnfb7q4tokwum4ju

Protein Crystallography in Drug Discovery [chapter]

T. Hogg, R. Hilgenfeld
2007 Comprehensive Medicinal Chemistry II  
Crystallography in Drug Discovery Protein Crystallography in Drug Discovery  ...  position in structure-based drug design (SBDD) (see 4.24 Structure-Based Drug Design -The Use of Protein Structure in Drug Discovery).  ...  There, he carried out crystallographic studies on ribosome-associated GTPbinding proteins including the bacterial drug target elongation factor Tu, and was awarded his PhD in 2001.  ... 
doi:10.1016/b0-08-045044-x/00111-5 fatcat:vdvh74jr5jgcdlvd3zzdw6uc4a

Applications of Solution NMR in Drug Discovery

Li Shi, Naixia Zhang
2021 Molecules  
Moreover, the NMR applications in protein-protein interaction (PPI) modulators development and the progress of in-cell NMR for drug discovery were also briefly summarized.  ...  In this manuscript, we reviewed the current progresses of NMR applications in fragment-based drug discovery, which were illustrated by multiple reported cases.  ...  Except for the conventional target-oriented drug discovery, targeting protein-protein interactions (PPIs) has been emerging as an attractive approach for drug development.  ... 
doi:10.3390/molecules26030576 pmid:33499337 fatcat:kyk3gf5djng2vdbkyqel2fvlz4

Selection of protein conformations for structure-based polypharmacology studies

Luca Pinzi, Fabiana Caporuscio, Giulio Rastelli
2018 Drug Discovery Today  
Teaser This review will focus on currently available methods for the selection of the most suitable protein conformations for multi-target structure-based drug design.  ...  affects structure-based drug design results.  In silico approaches for protein conformation selection are presented.  Examples of protein conformation selection for structure-based drug design are reported  ...  The article reflects only the authors' view and neither the European Commission nor the Research Executive Agency are responsible for any use that may be made of the information it contains.  ... 
doi:10.1016/j.drudis.2018.08.007 pmid:30099123 fatcat:wg2x3d6nk5budkn6iuc23hopbe

Target–drug interactions: first principles and their application to drug discovery

Sara Núñez, Jennifer Venhorst, Chris G. Kruse
2012 Drug Discovery Today  
In this review, we begin by introducing the basic principles of kinetics and thermodynamics of target-drug binding within the context of drug discovery.  ...  The utilization of the kinetic and thermodynamic signatures of preclinical leads is proving pivotal in their triage and rational optimization towards clinical candidates with maximal in vivo efficacy devoid  ...  Acknowledgements The authors acknowledge the help from Antoniou and McCormack for proof-reading the manuscript and Lange for valuable scientific discussions.  ... 
doi:10.1016/j.drudis.2011.06.013 pmid:21777691 fatcat:paqphwwlu5frxpgbalze2nqvdq

Computational Studies for Structure-Based Drug Designing Against Transmembrane Receptors: pLGICs and Class A GPCRs

Pavan V. Payghan, Indrani Bera, Dhananjay Bhattacharyya, Nanda Ghoshal
2018 Frontiers in Physics  
The crystal structures of integral membrane proteins (IMPs) are difficult to obtain.  ...  These proteins carry important biological functions and hence are attractive drug targets.  ...  All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. ACKNOWLEDGMENTS  ... 
doi:10.3389/fphy.2018.00052 fatcat:fuu4aqb6avbcpp6n26yb5qkaxm

The holistic integration of virtual screening in drug discovery

Yusuf Tanrikulu, Björn Krüger, Ewgenij Proschak
2013 Drug Discovery Today  
Furthermore, we identify challenges that lie ahead for the development of integrated VS campaigns.  ...  VS campaigns have become fully integrated into drug discovery campaigns, evenly matched and complementary to high-throughput screening (HTS) methods.  ...  a key aspect for future drug discovery success.  ... 
doi:10.1016/j.drudis.2013.01.007 pmid:23340112 fatcat:e4g4a5didrblblejccbhlkh7zi
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