Abstract
The phosphatidylinositol 3-kinase delta (PI3Kd) controls a range of cellular processes. Its overexpression is found in many human tumors. PI3Kd inhibitors are potential anticancer agents and anti-inflammatory agents for treatment of rheumatoid arthritis. Derivatives of ZSTK474, an effective inhibitor of PI3Kd, were screened virtually by computational docking for inhibitory activity towards PI3Kd. Some of modeled compounds showed better docking energies than ZSTK474 indicating that the former could be potent enzyme inhibitors. Additional binding energy was provided by extra ligand-protein interactions. Substituents in morpholine and benzimidazole rings cause increase and decrease of ligand-protein binding, respectively. Energetically favorable ZSTK474 derivatives satisfy Lipinski’s Rule of five which testifies to their druglikeness (absorption, distribution, metabolism and excretion) and possible pharmacological activity.
Highlights
The phosphatidylinositol 3-kinase delta (PI3K) is a lipid kinase related to class I PI3Ks and mainly presents in leukocytes [1]
The present study focuses on search of substituents which will increase the binding of ZSTK474 with PI3K
Docking for ZSTK474 led to a cluster (Fig. 1a, b) with binding energy of –9.5 kcal/mol
Summary
The PI3K (phosphatidylinositol 3-kinase delta) is a lipid kinase related to class I PI3Ks and mainly presents in leukocytes [1]. It has a physiological role in B-cell signaling, development and survival. Earlier developed smallmolecule ATP-competitive PI3K inhibitors had low affinity, instability, nonselectivity and toxicity that limited their clinical use [8]. Search of new inhibitors for PI3K has got a great attention and was directed to minimize undesired and often poorly understood toxic side effects, enhance potency, selectivity and pharmacological properties. A lot of structures, including TGX286 (8-(1-anilinoethyl)-6-methyl-2pyridin-4-ylchromen-4-one), PIK39 (5-chloro-3-(2methoxyphenyl)-2-(7H-purin-6-ylsulfanylmethyl)quinazolin-4-one), IC87114 (2-[(6-aminopurin-9yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin4-one), CAL101 (5-fluoro-3-phenyl-2-[(1S)-1-(7Hpurin-6-ylamino)propyl]quinazolin-4-one), ZSTK474 (4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine), NVPBEZ235
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