Structure-based identification of inhibitors disrupting the CD2–CD58 interactions

• Published in: Journal of computer-aided molecular design 2021-03, Vol.35 (3), p.337-353
• Main Authors: Tripathi, Neha, Leherte, Laurence, Vercauteren, Daniel P., Laurent, Adèle D.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animal Anatomy; Antigens; Binders; Binding Sites; CD2 Antigens - chemistry; CD58 Antigens - chemistry; Chemical Sciences; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Databases, Chemical; Drug Evaluation, Preclinical; Histology; Humans; Immune response; Immune system; In vitro methods and tests; Life Sciences; Ligands; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Morphology; Organic Chemicals - chemistry; Organic chemistry; Pharmacology; Physical Chemistry; Protein Binding; Screening; Structure-Activity Relationship; T-Lymphocytes
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-020-00369-z

The immune system has very intricate mechanisms of fighting against the invading infections which are accomplished by a sequential event of molecular interactions in the body. One of the crucial phenomena in this process is the recognition of T-cells by the antigen-presenting cells (APCs), which is initiated by the rapid interaction between both cell surface receptors, i.e. , CD2 located on T-cells and CD58 located on APCs. Under various pathological conditions, which involve undesired immune response, inhibiting the CD2–CD58 interactions becomes a therapeutically relevant opportunity. Herein we present an extensive work to identify novel inhibiting agents of the CD2–CD58 interactions. Classical molecular dynamics (MD) simulations of the CD2–CD58 complex highlighted a series of crucial CD58 residues responsible for the interactions with CD2. Based on such results, a pharmacophore map, complementary to the CD2-binding site of CD58, was created and employed for virtual screening of ~ 300,000 available compounds. On the ~ 6000 compounds filtered from pharmacophore mapping, ADME screening leads to ~ 350 molecules. Molecular docking was then performed on these molecules, and fifteen compounds emerged with significant binding energy (