Structural prediction of novel pyrazolo-pyrimidine derivatives against PIM-1 kinase: In-silico drug design studies

摘要

The PIM kinases are a family of serine/threonine kinase belongs to the Ca2+/calmodulin-dependent protein kinase (CAMK) group. Aberrations of PIM kinase pathway may be associated with the development of various types of cancer. In the present manuscript, pharmacophore modeling, 3D-QSAR and docking studies have been performed on pyrazolo-pyrimidine derivatives to identify the essential features required for the development of potential inhibitors. The phase developed pharmacophore hypothesis (ADRR_1) consist of the essential features such as, one hydrogen bond acceptor, one hydrogen bond donor, and two aromatic rings, required for the activity. The 3D-QSAR studies were performed by the using atom-based and field-based methods which generate high regression coefficients for the training (r(2) = 0.87; 0.96) and test (Q2 = 0.71; 0.69) sets, consecutively. The docking study showed good binding interactions with essential amino acids such as LYS67, GLU12, ASP128 and GLU171. The virtual screening studies have been performed through ZINC database by using pharmacophore ADRR_1, which produced 7006 drug like molecules. These molecules further proceed through different docking methodologies and screened four hit compounds namely, ZINC12941871, ZINC59456449, ZINC59456489, and ZINC59456444. The compound ZINC59456449 showed best docked pose (similar to crystal ligand) with docking scores, XP (-8.42 kcal/mol) and SP (-7.94 kcal/mol). The ADME and MMGBSA parameters showed the excellent value which may be used for the optimization of potent compounds. These results may further help to the scientists for the development of novel compounds against PIM-1 kinase. (c) 2020 Elsevier B.V. All rights reserved.