Identification of small molecule modulators of class II transactivator-I using computational approaches

• Published in: Journal of biomolecular structure & dynamics 2023-11, Vol.41 (17), p.8349-8361
• Main Authors: Nagasubramanian, Kishore, Jha, Shanker, Rathore, Anuranjan Singh, Gupta, Krishnakant
• Format: Article
• Language: English
• Subjects: CIITA-I interactors; Class II transactivator (CIITA); hyper inflammation; major histocompatibility complex II (MHC II); molecular docking; simulation studies on CIITA
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2022.2133011

Major histocompatibility complex II (MHCII), a mediator of the innate and adaptive immune system, plays a central role in regulating inflammation and its progression. Class II transactivator (CIITA) is a master regulator of MHCII expression and controls antigen presentation followed by T-cell activation. Regulation of inflammation by modulation of CIITA has been suggested as a promising intervention for several disorders, including neuroinflammation, rheumatoid arthritis and other autoimmune diseases. This study aimed to (i) identify possible pharmacological agents which could bind to and inhibit isoform I of CIITA (CIITA-I) and (ii) determine their strength of interactions. The structure of CIITA-I isoform was predicted using phyre2 and refined via 3D refine. Loops were refined using ModBase, followed by quality assessment based on ERRAT value. The refined 3D structure was subjected to docking via Maestro (from Schrodinger) using glide module against small molecule databases. Molecules having the least glide score and favorable ADME properties were subjected to molecular simulation by GROMACS. We used the 3D refined structure of CIITA-I, with a score of 83.4% in ERRAT for docking studies. The ligand 4-(2-((6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) thio) acetamido) benzamide (ZINC5154833), showed maximum glide score (−6.591) followed by N-[4-(3-oxo-3-{4-[3-(trifluoromethyl) phenyl] piperazin-1-yl} propyl)-1,3-thiazol-2-yl] benzamide (F5254-0161, glide score −6.41). Simulation studies using GROMACS showed F5254-0161 to have a more stable interaction with CIITA-I. Based on our analysis, we propose ZINC5154833 and F5254-0161 as potential modulators for CIITA-I. Communicated by Ramaswamy H. Sarma