3D-QSAR and Pharmacophore modeling of 3,5-disubstituted indole derivatives as Pim kinase inhibitors
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ORIGINAL RESEARCH
3D-QSAR and Pharmacophore modeling of 3,5-disubstituted indole derivatives as Pim kinase inhibitors Bhushan D. Varpe 1 & Shailaja B. Jadhav 2 & Bandoo C. Chatale 3 & Anil S. Mali 1 & Shravan Y. Jadhav 4 & Amol A. Kulkarni 1 Received: 19 December 2019 / Accepted: 28 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Indole derivatives are reported in the literature for their excellent kinase inhibition activity, so understanding their structural requirement is important. For their further development, ligand-based pharmacophore, atom and field-based 3D-QSAR, and ADME studies of the 3, 5-disubstituted indole derivatives were carried out. Ligand-based pharmacophore, atom and fieldbased 3D-QSAR models were developed using the Phase module of Schrodinger suite. In silico ADME and drug-likeness properties were studied using the Quikprop module of Schrodinger suite. Five-point pharmacophore model (DHRRR _1) with one hydrogen bond donor (D), one hydrophobic site (H), and three aromatic rings (R) was developed. 3D-QSAR models yielded with good statistical results as the models were characterized by PLS factors 4 and validated by parameters like R2, R2 CV, Stability, F-value, P value, RMSE, Q2, and Pearson-r. Keywords 3,5-disubstituted indole derivatives . 3D-QSAR . Docking . Pharmacophore modeling . ADME
Introduction Proto-oncogene serine/threonine-protein kinase (Pim-1) is an enzyme that is encoded by the Pim-1 gene [1, 2]. Pim proteins are of three forms Pim-1, Pim-2, and Pim-3, which regulate various signaling pathways in the development of cancer. [3] Pim kinases are often activated in various downstream substrates that are thought to contribute to tumor growth and survival in both hematologic and solid cancers [4]. The Pim-1 oncogene is identified as being the locus most frequently triggered by the Moloney murine leukemia virus in relation to murine T cell lymphomas [5].
* Amol A. Kulkarni [email protected] 1
DKSS’s Institute of Pharmaceutical Sciences and Research, Swami-Chincholi, Pune, Maharashtra 413130, India
2
PES’s Modern College of Pharmacy, Nigdi, Pune, Maharashtra 411044, India
3
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Mumbai 400019, India
4
Department of Chemistry, DBF Dayanand College of Arts & Science, 413002, Solapur, Maharashtra, India
Pim isoforms have different levels of expression and distinct roles. All three Pim genes in cancer, there is compelling evidence of a compensatory mechanism [6–9]. Adenosine triphosphate-competitive Pim inhibitors, SGI1776, AZD1208, TP-36544, and LGH447 are in clinical trials for the treatment of acute prostate cancer, myelogenous leukemia, and lymphoma (Fig. 1) [10]. Indole derivatives are widely studied for their kinase inhibitory activity as reported in literature. [11–14] The novel series of meridianin C derivatives reported in the literature [15] and have shown strong inhibitory activities against Pim-1 and Pim-3 kinases that encouraged
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