Structure-based virtual screening toward the discovery of novel inhibitors for impeding the protein-protein interaction between HIV-1 integrase and human lens epithelium-derived growth factor (LEDGF/p75)
Umesh Panwar
Sanjeev Kumar Singh
10.6084/m9.figshare.5527858.v1
https://tandf.figshare.com/articles/journal_contribution/Structure-based_virtual_screening_toward_the_discovery_of_novel_inhibitors_for_impeding_the_protein-protein_interaction_between_HIV-1_integrase_and_human_lens_epithelium-derived_growth_factor_LEDGF_p75_/5527858
<p>HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.</p>
2017-10-23 13:59:01
AIDS
HIV-1 integrase
human LEDGF/p75
protein–protein interaction
virtual screening
molecular docking and simulation
AIDS – Acquired immunodeficiency syndrome
ADME – Absorption, Distribution, Metabolism, Excretion
CCD – catalytic core domain
CNS – Central Nervous System
DFT – Density Functional Theory
IBD – IN-binding domain
IFD – Induced fit docking
IN – Integrase
LEDGF/p75 – lens epithelium-derived growth factor
LEDGINs – lens epithelium-derived growth factor Integrase Inhibitor
MDS – Molecular dynamics simulation
MM-GBSA – Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation
PPI – protein-protein interaction
VS – Virtual screening