In silico quest of selective naphthyl-based CREBBP bromodomain inhibitor.

The reader proteins like bromodomains have recently gained increased attentions in the area of epigenetic drug discovery, as they are the potent regulators in gene transcription process. Among the other bromodomains, cAMP response element-binding protein (CREB) binding protein or CREBBP bomodomain involved in various cancer progressions and therefore, efforts to develop specific inhibitors of CREBBP bomodomain are of clinical value. In this study, we tried to identify selective CREBBP bromodomain inhibitor, which was accomplished by using molecular docking, free energy calculation and molecular dynamics (MD) simulation studies, considering a series of naphthyl based compounds. The docking procedure was validated by comparing root mean square deviations (RMSDs) of crystallographic complex to docked complex. Favorable electrostatic interactions with the Arg1173 side chain were considered to attain selectivity for CREBBP bromodomain over other human bromodomain subfamilies. We found that naphthyl-based compounds have greater binding affinities towards the CREBBP bromodomain, and formed non-bonded interactions with various side chain residues that are important for bromodomain inhibition. From detailed investigation by induced fit docking, compound 31 was found to have favorable electrostatic interactions with the Arg1173 side chain by forming conventional hydrogen bonds. This result was further confirmed by analyzing hydrogen bond occupancy and bonding distance during the molecular dynamics simulation. We believe that these findings offer useful insight for the designing of target specific new bromodomain inhibitor and also promote further structure guided synthesis of analogues for identification of potent CREBBP bromodomain inhibitors as well as detailed in vitro and in vivo analyses.

Molecular Simulation Studies of 3,3'-Diindolylmethane as a Potent MicroRNA-21 Antagonist.

OBJECTIVE: In recent decades, the overexpression of microRNA-21 (miR-21) is found to be progressively linked with many diseases such as different types of cancers, cardiovascular diseases, and inflammation. Thereby, it has become an attractive target for pharmacological and genetic modulation in various diseases, and also for overcoming the resistance to chemotherapy in several cancers. Here, in this study, the role of molecular therapeutics of 3,3'-diindolylmethane (DIM) has been investigated for its ability to bind with the precursor miRNA as a target of miR-21 (hsa-mir-21), which may alter the catalyzation process of dicer, a RNase III enzyme, involved in miRNA transcription. METHODS: In this context, the present study describes the potential binding and the structure alteration properties of DIM to precursor miR-21 (pre-miR-21) through Molecular Docking and Molecular Dynamics simulation techniques. RESULTS: As a corollary, DIM formed both non-bonded and covalent interactions with the bases of pre-miR, while covalent interaction with guanine in the 6th position was found to be consensus in molecular dynamics simulation. Furthermore, the stability of both DIM and pre-miR-21 was found to be inversely correlated to each other in binding condition. CONCLUSION: This result indicates that DIM can be used in target-based therapy and also as a lead for further development of potent small molecule miRNA antagonist.