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Abstract : The present work was envisioned to design a series of novel 7Azaindole derivatives containing pyrimidine scaffolds for its inhibition towards BRD4. In-silico studies such as docking, ADMET, calculation of molecular properties and Toxicity studies were performed using Accelery’s Discovery studio 3.5. Most of the designed compounds were found to have better binding towards BRD4 through hydrogen bonding with amino acids such as ARG 150, SER 148, ASP 129, ILE 263 and pi interactions with better –C-Docker interaction energy. Most of the compounds were in the expected range of the other above mentioned in-silico studies. Among all the designed ligands, A16 possess 3, 4, 5-trimethoxy phenyl substituent found to have better binding affinity with BRD4 with all the virtual studies values within the expected range. Saiprabha VN, Giles D, Sharanabasava UR Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Achit Nagar Post, Bengaluru-560107 Submission: 23 November 2019 Accepted: 29 November 2019 Published: 30 December 2019 www.ijppr.humanjournals.com(link is external) Citation: Saiprabha VN et al. Ijppr.Human, 2019; Vol. 17 (1): 13-24. 14 INTRODUCTION Cancer is one of the dreadful disease which is having a serious consequence throughout the world. Bromodomain containing protein family has been emerged as an important target in cancer research. Bromodomain is a protein domain, constitutes 110 amino acids which are responsible for the recognition of acetylated lysine of histones. They are epigenetic readers and the family mainly consists of BRD1, BRD2, BRD3, BRD4 and Bromodomain Extra Terminal (BRDT). The structural features of all the bromodomains include two N-terminal bromodomains and an extra C-terminal domain (ET). Among the family, BRD4 has been extensively concentrated more in research field and it has been implicated in various types of cancers such as breast, cervical, ovarian, bone, etc. The structural features of BRD4 constitutes a highly conserved N-terminal bromodomain; BD1 and BD2, an extra terminal domain and a C-terminal domain. By interacting with acetylated chromatin and non-histone proteins, BRD4 has been involved mainly in the regulation of DNA replication, transcription and cell cycle progression. BRD4 structure mainly consists of four α helices (αZ, αA, αB, and αC) which are separated by various loop regions of ZA and BC which forms the hydrophobic cavity which is responsible for the recognition of acetylated lysines of histones. BRD4 inhibitors could block the interactions between BRD4 and acetyl lysine binding site and should be best in mimicking acetyl lysine and competing with acetyl lysine binding site to bind with BRD4. BC loop which constitutes a hydrophobic region is also playing an important role in BRD4 binding affinities. Azaindoles have gained a considerable interest among medicinal chemists owing to their physicochemical and pharmacological properties. As a bio isostere of purine or indole, they were found to facilitate solubility enhancement, reduction of lipophilicity, favorable target binding and improvement of ADME as well as toxicity parameters. Because of its unique ability to accept and donate hydrogen bonds, 7 7-azaindole moiety has been found to exhibit a wide variety of pharmacological actions such as anticancer, 8 anti-inflammatory, 9 antimicrobial etc. Pyrrolopyridine structure constitutes a pyrole and pyrimidine ring mainly have four isomers and among them (4, 5, 6 and 7 azaindole), 7-azaindole found to exhibit various pharmacological activities. In addition, the binding between the ligand and the receptor can be enhanced by the bioisosteric replacement of indole ring with an azaindole ring by the formation of an extra hydrogen bond and thus an increase in the pharmacological activity. So hereby in the present work, we designed a series of 7-azaindole derivatives and www.ijppr.humanjournals.com(link is external) Citation: Saiprabha VN et al. Ijppr.Human, 2019; Vol. 17 (1): 13-24. 15 explored their binding interaction with the bromodomain containing protein 4 and thus inhibition. This work was mainly planned to design derivatives of 7-azaindole for its binding affinity towards BRD4 and also to evaluate in-silico parameters such as ADME and toxicity. MATERIALS AND METHODS Virtual screening studies are mainly performed to identify potential lead compounds from a set of database of inactive compounds. The main aim of virtual screening is to reduce the number of ligands to be screened experimentally and thus by reducing the number of false positives. Docking is mainly accomplished to study the effect of binding interaction between the ligand and the receptor and can generate good poses of ligand in an active site of the receptor. Molecular properties Molecular properties considered to be an important criterion during designing of ligands. In the present paper, molecular properties such as molecular weight, A log P, H acceptors, H donors, molecular fractional polar surface area were calculated using Accelery’s Discovery studio 3.5 and the results are depicted in table 1. Molecular Docking Studies Docking study was mainly carried out to analyze the interaction between the receptor and the designed ligands and the study was carried out using Discovery studio 3.5. Docking mainly constitutes protein preparation, ligand preparation and receptor ligand interaction using different programmes. In the present paper, C-Dock programme with CHARMm forcefield was executed for running docking. a. Protein preparation The X-ray crystallographic structure of BRD4 (PDB id: 4HY3), was downloaded from RCSB Protein Data Bank with a resolution of 2.8Å. For the preparation of protein, 110 amino acids with A chain was retained, water molecules were deleted and hydrogens were added. The protein was prepared by employing MACROMOLECULES tool in the Discovery studio. The prepared protein was subjected to minimization using CHARMm forcefield. www.ijppr.humanjournals.com(link is external) Citation: Saiprabha VN et al. Ijppr.Human, 2019; Vol. 17 (1): 13-24. 16 b. Ligand preparation The structures of the designed ligands were drawn in ChemDraw and were uploaded in Discovery studio in mol format. They were subjected to ligand preparation and minimization using SMALL MOLECULES tool in the Discovery studio. c. Molecular Docking The minimized ligands were docked into the active site of the receptor using CHARMm force field by executing C-Docker programme in Discovery studio. C-Docker energy, C-Docker interaction energy, Hydrogen bonding and the amino acids involved in binding with the receptor were extensively studied and the results are depicted in table 2