Identification of novel PI3Kδ inhibitors by docking, ADMET prediction and molecular dynamics simulations

BACKGROUND Phosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects. METHOD Computer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor. RESULTS Based on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: -12.175 kcal/mol, cdocker binding energy: -42.975 kcal/mol and ΔGbind value: -90.457 kcal/mol) and BAS 00227397 (Glide score: -10.988 kcal/mol, cdocker binding energy: -39.3376 kcal/mol and ΔGbind value: -81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand's behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket. CONCLUSION Compound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.

[1]  Quentin Liu,et al.  Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents. , 2016, European journal of medicinal chemistry.

[2]  Dominique Douguet,et al.  Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors , 2017, Scientific Reports.

[3]  Carsten Denkert,et al.  Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). , 2017, European journal of cancer.

[4]  Yi Liu,et al.  The p110δ crystal structure uncovers mechanisms for selectivity and potency of novel PI3K inhibitors , 2009, Nature chemical biology.

[5]  Yongjin Xu,et al.  Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model. , 2016, Bioorganic & medicinal chemistry letters.

[6]  Matthias Theobald,et al.  Idelalisib impairs TREM-1 mediated neutrophil inflammatory responses , 2018, Scientific Reports.

[7]  Jacqueline C Barrientos,et al.  Can umbralisib bring PI3Kδ out of the shadows? , 2018, The Lancet. Oncology.

[8]  W. Sellers,et al.  Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor , 2011, Molecular Cancer Therapeutics.

[9]  Norikazu Masuda,et al.  Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[10]  Margarita Gutiérrez,et al.  Design, facile synthesis, and evaluation of novel spiro- and pyrazolo[1, 5-c]quinazolines as cholinesterase inhibitors: Molecular docking and MM/GBSA studies , 2018, Comput. Biol. Chem..

[11]  Bryan T Hennessy,et al.  PI3K inhibition to overcome endocrine resistance in breast cancer , 2018, Expert opinion on investigational drugs.

[12]  Dejan Juric,et al.  Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Nadine Houédé,et al.  Enterocolitis in Patients with Cancer Treated with Docetaxel. , 2018, Anticancer research.

[14]  Jiaguo Lv,et al.  Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma. , 2016, Bioorganic & medicinal chemistry.

[15]  N. Meanwell.  Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. , 2011, Chemical research in toxicology.

[16]  Tahmeena Khan,et al.  Exploring the novel heterocyclic derivatives as lead molecules for design and development of potent anticancer agents. , 2018, Journal of molecular graphics & modelling.

[17]  Bo Yang,et al.  Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors. , 2015, European journal of medicinal chemistry.

[18]  Yanli Wang,et al.  Structural insights of a PI3K/mTOR dual inhibitor with the morpholino-triazine scaffold , 2016, Journal of Computer-Aided Molecular Design.

[19]  Feroz Khan,et al.  Virtual screening, Docking, ADMET and System Pharmacology studies on Garcinia caged Xanthone derivatives for Anticancer activity , 2018, Scientific Reports.

[20]  Jiaxin Fan,et al.  Mechanism of modulation through PI3K-AKT pathway about Nepeta cataria L.’s extract in non-small cell lung cancer , 2017, Oncotarget.

[21]  H. Adeola,et al.  A multi-centre evaluation of oral cancer in Southern and Western Nigeria: an African oral pathology research consortium initiative , 2017, The Pan African medical journal.

[22]  Pritish Kumar Varadwaj,et al.  Structural insights into conformational stability of both wild-type and mutant EZH2 receptor , 2016, Scientific Reports.

[23]  Li Fu,et al.  Combined inhibition of PI3Kδ and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia. , 2018, Cancer letters.

[24]  Gopinath Ganji,et al.  A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors , 2017, Clinical Cancer Research.

[25]  François Bertucci,et al.  PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. , 2017, European journal of cancer.

[26]  Canhui Zheng,et al.  Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor. , 2016, European journal of medicinal chemistry.

[27]  Dejan Juric,et al.  First‐in‐human trial of the PI3Kβ‐selective inhibitor SAR260301 in patients with advanced solid tumors , 2018, Cancer.

[28]  Takahiro Arai,et al.  Development of novel PET probes targeting phosphatidylinositol 3-kinase (PI3K) in tumors. , 2016, Nuclear medicine and biology.

[29]  Jean-Pierre Marquette,et al.  Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. , 2014, Journal of medicinal chemistry.

[30]  Roberto Piñeiro,et al.  Molecules in medicine mini-review: isoforms of PI3K in biology and disease , 2015, Journal of Molecular Medicine.

[31]  D. Erdmann,et al.  Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials , 2014, Molecular Cancer Therapeutics.

[32]  Pritish Kumar Varadwaj,et al.  Novel DOT1L ReceptorNatural Inhibitors Involved in Mixed Lineage Leukemia: a Virtual Screening, Molecular Docking and Dynamics Simulation Study. , 2015, Asian Pacific journal of cancer prevention : APJCP.

[33]  Prashant Joshi,et al.  6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors. , 2016, European journal of medicinal chemistry.

[34]  Ying Ma,et al.  Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics , 2018, Comput. Biol. Chem..

[35]  Shashi Bhushan,et al.  Modulation of glycolysis and lipogenesis by novel PI3K selective molecule represses tumor angiogenesis and decreases colorectal cancer growth. , 2016, Cancer letters.

[36]  Jun Zhang,et al.  Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan , 2017, Journal of biomolecular structure & dynamics.

[37]  Michael R Savona,et al.  Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. , 2018, The Lancet. Oncology.

[38]  P. Varadwaj,et al.  Molecular docking and dynamics simulation study of flavonoids as BET bromodomain inhibitors , 2017, Journal of biomolecular structure & dynamics.

[39]  Po-Chang Chiang,et al.  An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kδ Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs. , 2018, Journal of pharmaceutical sciences.

[40]  Pascal Furet,et al.  Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors. , 2016, ACS medicinal chemistry letters.

[41]  Doriano Fabbro,et al.  Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. , 2013, Bioorganic & medicinal chemistry letters.

[42]  Latesh Lad,et al.  Structural, Biochemical, and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-Kinase δ* , 2015, The Journal of Biological Chemistry.

[43]  R. Aguiar,et al.  Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδ in Mature B-cell Malignancies , 2017, Clinical Cancer Research.

[44]  Brian D Ross,et al.  Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K). , 2016, Journal of medicinal chemistry.