NDLI: Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation

Content Provider	Springer Nature Link
Author	Machicado, Claudia López Lla, Jon Cuesta López, Santiago Bue, Marta Sancho, Javier
Copyright Year	2005
Abstract	Proteins could be used to carry and deliver small compounds. As a tool for designing ligand binding sites in protein cores, a three-step virtual screening method is presented that has been optimised using existing data on T4 lysozyme complexes and tested in a newly engineered cavity in flavodoxin. The method can pinpoint, in large databases, ligands of specific protein cavities. In the first step, physico-chemical filters are used to screen the library and discard a majority of compounds. In the second step, a flexible, fast docking procedure is used to score and select a smaller number of compounds as potential binders. In the third step, a finer method is used to dock promising molecules of the hit list into the protein cavity, and an optimised free energy function allows discarding the few false positives by calculating the affinity of the modelled complexes. To demonstrate the portability of the method, several cavities have been designed and engineered in the flavodoxin from Anabaena PCC 7119, and the W66F/L44A double mutant has been selected as a suitable host protein. The NCI database has then been screened for potential binders, and the binding to the engineered cavity of five promising compounds and three tentative non-binders has been experimentally tested by thermal up-shift assays and spectroscopic titrations. The five tentative binders (some apolar and some polar), unlike the three tentative non-binders, are shown to bind to the host mutant and, importantly, not to bind to the wild type protein. The three-step virtual screening method developed can thus be used to identify ligands of buried protein cavities. We anticipate that the method could also be used, in a reverse manner, to identify natural or engineerable protein cavities for the hosting of ligands of interest.
Starting Page	421
Ending Page	443
Page Count	23
File Format	PDF
ISSN	0920654X
Journal	Journal of Computer-Aided Molecular Design
Volume Number	19
Issue Number	6
e-ISSN	15734951
Language	English
Publisher	Kluwer Academic Publishers
Publisher Date	2005-01-01
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	flavodoxin flexible docking ligand binding protein cavity protein stability reverse docking virtual screening Computer Applications in Chemistry Physical Chemistry Animal Anatomy / Morphology / Histology
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Physical and Theoretical Chemistry Computer Science Applications

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK

A reverse combination of structure-based and ligand-based strategies for virtual screening

Multiple ligand docking by Glide: implications for virtual second-site screening

Ligand docking and binding site analysis with PyMOL and Autodock/Vina

Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments

Unsupervised guided docking of covalently bound ligands

Knowing when to give up: early-rejection stratagems in ligand docking

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Distilling the essential features of a protein surface for improving protein-ligand docking, scoring, and virtual screening

Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation

Similar Documents

Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK

A reverse combination of structure-based and ligand-based strategies for virtual screening

Multiple ligand docking by Glide: implications for virtual second-site screening

Ligand docking and binding site analysis with PyMOL and Autodock/Vina

Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments

Unsupervised guided docking of covalently bound ligands

Knowing when to give up: early-rejection stratagems in ligand docking

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Distilling the essential features of a protein surface for improving protein-ligand docking, scoring, and virtual screening

Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation