title: Computational discovery of novel HIV-1 entry inhibitors based on potent and broad neutralizing antibody VRC01.
abstract: Computational prediction of novel HIV-1 entry inhibitors presenting peptidomimetics of broadly neutralizing antibody (bNAb) VRC01 was carried out based on the analysis of the X-ray complex of this antibody antigen-binding fragment with the HIV envelope gp120 core. Using these empirical data, peptidomimetic candidates of bNAb VRC01 were identified by a public web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to gp120 were generated by molecular docking. At the final point, the stability of the complexes of these molecules with gp120 was estimated by molecular dynamics and binding free energy calculations. The calculations identified six molecules exhibiting a high affinity to the HIV-1 gp120 protein. These molecules were selected as the most probable peptidomimetics of bNAb VRC01. In a mechanism similar to that of bNAb VRC01, these compounds were predicted to block the functionally conserved regions of gp120 critical for the HIV-1 binding to cellular receptor CD4. The docked structures of the identified molecules with gp120 do not undergo substantial rearrangements during the molecular dynamics simulations, in agreement with the low values of free energy of their formation. Based on these findings, the selected compounds are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics.
authors: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Street 5/2, 220141 Minsk, Belarus. Electronic address: andrianov@iboch.bas-net.by.
authors: Alexander M
authors: AM
authors: Andrianov
authors: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Street 5/2, 220141 Minsk, Belarus.
authors: Ivan A
authors: IA
authors: Kashyn
authors: United Institute of Informatics Problems, National Academy of Sciences of Belarus, Surganov Street 6, 220012 Minsk, Belarus.
authors: Alexander V
authors: AV
authors: Tuzikov
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D057134:Antibodies, Neutralizing / Q000737:chemistry*; D001665:Binding Sites; D000080908:Broadly Neutralizing Antibodies; D015704:CD4 Antigens / Q000737:chemistry; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D057786:Peptidomimetics / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface; D053586:Virus Internalization
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D057786:Peptidomimetics; C578595:VRC01 monoclonal antibody; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: Anti-HIV-1 therapeutics; HIV-1 gp120 protein; Molecular modeling; Neutralizing antibody VRC01; Peptidomimetics; Virtual screening