title: Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases.
abstract: Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen-antibody (Ag - Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag - Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.
authors.affiliation: a Biomedical Informatics Centre, National Institute of Pathology - ICMR , New Delhi , India and.
authors.forename: Rashi
authors.initials: R
authors.lastname: Verma
authors.affiliation: a Biomedical Informatics Centre, National Institute of Pathology - ICMR , New Delhi , India and.
authors.forename: Monika
authors.initials: M
authors.lastname: Yadav
authors.affiliation: a Biomedical Informatics Centre, National Institute of Pathology - ICMR , New Delhi , India and.
authors.forename: Dibyabhaba
authors.initials: D
authors.lastname: Pradhan
authors.affiliation: b Bioinformatics Infrastructure Facility, University of Kalyani , Kalyani, West Bengal , India.
authors.forename: Rajabrata
authors.initials: R
authors.lastname: Bhuyan
authors.affiliation: a Biomedical Informatics Centre, National Institute of Pathology - ICMR , New Delhi , India and.
authors.forename: Shweta
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: a Biomedical Informatics Centre, National Institute of Pathology - ICMR , New Delhi , India and.
authors.forename: Arnab
authors.initials: A
authors.lastname: Nayek
authors.affiliation: a Biomedical Informatics Centre, National Institute of Pathology - ICMR , New Delhi , India and.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Jain
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000737:chemistry* / Q000378:metabolism; D007854:Lead / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D007854:Lead; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C000592400:olokizumab
keywords: Interleukin-6; antigen–antibody docking; autoimmune and inflammatory diseases; computer-aided antibody engineering; olokizumab