title: Computational Design of Hypothetical New Peptides Based on a Cyclotide Scaffold as HIV gp120 Inhibitor.
abstract: Cyclotides are a family of triple disulfide cyclic peptides with exceptional resistance to thermal/chemical denaturation and enzymatic degradation. Several cyclotides have been shown to possess anti-HIV activity, including kalata B1 (KB1). However, the use of cyclotides as anti-HIV therapies remains limited due to the high toxicity in normal cells. Therefore, grafting anti-HIV epitopes onto a cyclotide might be a promising approach for reducing toxicity and simultaneously improving anti-HIV activity. Viral envelope glycoprotein gp120 is required for entry of HIV into CD4+ T cells. However, due to a high degree of variability and physical shielding, the design of drugs targeting gp120 remains challenging. We created a computational protocol in which molecular modeling techniques were combined with a genetic algorithm (GA) to automate the design of new cyclotides with improved binding to HIV gp120. We found that the group of modified cyclotides has better binding scores (23.1%) compared to the KB1. By using molecular dynamic (MD) simulation as a post filter for the final candidates, we identified two novel cyclotides, GA763 and GA190, which exhibited better interaction energies (36.6% and 22.8%, respectively) when binding to gp120 compared to KB1. This computational design represents an alternative tool for modifying peptides, including cyclotides and other stable peptides, as therapeutic agents before the synthesis process.
authors.affiliation: Bioinformatics and Systems Biology program, King Mongkut's University of Technology Thonburi (KMUTT), Bang Khun Thian, Bangkok, 10150, Thailand.
authors.forename: Apiwat
authors.initials: A
authors.lastname: Sangphukieo
authors.affiliation: Pilot Plant Development and Training Institute, KMUTT (Bang Khun Thian), Bangkok, 10150, Thailand.
authors.forename: Wanapinun
authors.initials: W
authors.lastname: Nawae
authors.affiliation: Bioinformatics and Systems Biology program, King Mongkut's University of Technology Thonburi (KMUTT), Bang Khun Thian, Bangkok, 10150, Thailand.
authors.forename: Teeraphan
authors.initials: T
authors.lastname: Laomettachit
authors.affiliation: School of Information Technology, KMUTT, Bang Mod, Thung Khru, Bangkok 10140, Thailand.
authors.forename: Umaporn
authors.initials: U
authors.lastname: Supasitthimethee
authors.affiliation: Bioinformatics and Systems Biology program, King Mongkut's University of Technology Thonburi (KMUTT), Bang Khun Thian, Bangkok, 10150, Thailand; Biotechnology program, School of Bioresources and Technology, KMUTT (Bang Khun Thian), Bangkok, 10150, Thailand.
authors.forename: Marasri
authors.initials: M
authors.lastname: Ruengjitchatchawalya
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D047169:Cyclotides / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides; D006678:HIV / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D019380:Anti-HIV Agents; D047169:Cyclotides; D004220:Disulfides; D015699:HIV Envelope Protein gp120; D010456:Peptides, Cyclic; C091930:kalata B1