Table 3.

Summarizing the computational tools for structure-based focused library generation

Approach	Name	Description	Case study examples	URL
Ligand binding site	3DLigandSite [59]	The web server identifies ligand binding site via MSA and clustering algorithm.	Target T0483 in CASP8	http://www.sbg.bio.ic.ac.uk/∼3dligandsite/
	ProBiS [60, 61]	The web server detects binding site using MSA and characterizes it using local structural pairwise alignment.	Biotin carboxylase, TATA binding protein [60], D-alanine–D-alanine ligase, Protein kinases C [61]	http://probis.cmm.ki.si/
	ProBiS-database [64]	The database provides structurally similar protein binding site using ProBiS algorithm.	Cytochrome c [64]	http://probis.cmm.ki.si/?what=database
	SiteComp [62]	The web server characterizes ligand binding site using molecular interaction descriptors.	Cyclooxygenase, adenylate kinase [62]	http://scbx.mssm.edu/sitecomp/sitecomp-web/Input.html
	TRITON [65, 66]	The method facilitates to model mutant, dock ligand in the protein and calculates reaction pathways for the characterization of protein-ligand interactions using Semi-empirical quantum-mechanics approach.	PA-IIL lectin and its mutants [65]	http://www.ncbr.muni.cz/triton/description.html
Protein interaction	PIC [68]	The web server calculates the molecular interactions using published criteria.	-	http://pic.mbu.iisc.ernet.in/job.html
	COCOMAPS [69]	The web server analyzes and visualizes interfaces in biological complexes using intermolecular contact maps based on distance or physicochemical properties.	Hen egg lysozyme interaction with two antibodies [69]	https://www.molnac.unisa.it/BioTools/cocomaps/
Residue depth and stability	DEPTH [70]	The web server predicts binding cavity and mutational effect on protein stability using residue depth and solvent accessible surface area.	West Nile Virus NS2B/NS3 protease [70]	http://mspc.bii.a-star.edu.sg/tankp/intro.html
	SRIde [71]	The web server predicts the contribution of residues in protein stability using interactions with its spatial neighbors and their evolutionary conservation.	TIM-barrel proteins [103]	http://sride.enzim.hu/
Protein surface and interface	Patch finder plus [72]	The web server identifies large positively charged electrostatic patches on protein surface using Poisson Boltzmann electrostatic potential.	DNA binding domain of TATA binding protein [72]	http://pfp.technion.ac.il/
	ConPlex [73]	The web server performs evolutionary conservation analysis of the protein complex.	Rho–RhoGAP complex [73]	http://sbi.postech.ac.kr/ConPlex/
Protein flexibility	RosettaBackrub [81]	The web server performs flexible backbone modeling using Backrub [104] method to design tolerated protein sequences.	hGH-hGHr interface [105]	https://kortemmelab.ucsf.edu/backrub/cgi-bin/rosettaweb.py?query=index
	tCONCOORD [83]	The method generates conformation ensemble and transitions using geometrical constrains based prediction of protein conformational flexibility.	Osmoprotection protein [83]	http://wwwuser.gwdg.de/~dseelig/tconcoord.html
	FlexPred [84]	The web server predicts residue flexibility in the protein using SVM approach.	Human PrP [106]	http://flexpred.rit.albany.edu/
	ElNemo [92]	The web server predicts large amplitude motions in the protein using NMA.	HIV-1 protease, E. coli membrane channel protein TolC	http://igs-server.cnrs-mrs.fr/elnemo/index.html
	WEBnm@ [93]		Calcium ATPase [93]	http://apps.cbu.uib.no/webnma/home
	FlexServ [94]	The web server determines and analyzes protein flexibility using coarse-grained modeling approach.	-	http://mmb.pcb.ub.es/FlexServ/input.php
	HINGEprot [95]	The web server detects hinge region in the protein using both GNM and ANM.	Calmodulin protein, hemoglobin [95]	http://www.prc.boun.edu.tr/appserv/prc/hingeprot/
	DynDom3D [98]	The web server predicts domain motions using conformational changes in the protein.	Hemoglobin, 70S ribosome [98]	http://fizz.cmp.uea.ac.uk/dyndom/3D/