Molecular docking

β-Lapachone (β-Lap) is a naturally occurring ortho-naphthoquinone found in the heartwood of Handroanthus impetiginosus and other lapacho trees. The compound has been studied extensively due to its promising anticancer potential in cancer cells with high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1). Reduction of β-Lap by NQO1 leads to the formation of a highly unstable hydroquinone intermediate which undergoes oxidation in a futile redox cycle, generating excessive amounts of ROS. The resultant oxidative stress can lead to DNA damage, hyperactivation of PARP1, reduction of NAD+ and ATP levels and cell death in cancer cells. Although β-Lap exhibits promising pharmacological effects, its poor solubility in water, problems with formulation and pharmacokinetics, possible toxic effects associated with dosing and limited therapeutic window limit the clinical applications of the parent compound. Therefore, various modifications of β-Lap structure were performed using the arylamino, alkoxy, thiosemicarbazone, oxime and prodrug strategies. Computer-assisted drug design approaches such as molecular docking, electronic-structure calculation and ADMET predictions serve as additional methods of selection of promising β-Lap derivatives before synthesis and testing. The present review gives a summary of the chemistry, physicochemical properties, SAR, pharmacology, synthetic and computational approaches to β-Lap and its derivatives [1-3,6]. The review was performed on published scientific papers based on β-lapachone, structural derivatives of β-lapachone, anticancer potential, molecular docking, and computational ADMET study. β-Lapachone was taken into account as the main parent compound, and structural derivatives, including arylamino, alkoxy, oxime, thiosemicarbazone, and other groups, were discussed. The computational methods, including molecular docking, were considered for the assessment of the interaction between the ligands and their targets (proteins) involved in the process of cancer development such as NQO1 and Topoisomerase IIα. Binding interactions, docking score, hydrogen bonding, hydrophobic, and π-π interactions were studied according to the reported studies. Besides, the pharmacokinetic and toxicity properties were also evaluated through ADMET prediction to obtain better anticancer agents [1,4,6,7]

The given title proposed with the aim to synthesize some novel benzylidene substituted benzodiazepine analogue to evaluate GABAA receptor inhibitory activity. Molecular docking simulation studies were also performed on life molecular suite software. All compounds found to possess good dock score, but varied in formation of intermolecular complexes at the receptor site. Bonding interactions like hydrogen bonds, hydrophilic bonds and pi-interactions of the ligand library with receptor binding site were considered as parameter for synthesis of selected and potent molecules. Diazepam to be selected as the reference compound and included in ligand library to ran simultaneously. Diazepam found to develop two hydrogen bonds with TYR 106A amino acid residue whereas π-π stacking interaction with TYR 106A and PHE 3A protein moiety. It is capable to form hydrophobic interactions with PHE 104A, PHE 3A, VAL 4A, ILE 32A, TYR 6A, TYR 5A, LYS 6A, and ARG 14A.  Most of the proposed compounds interacted in similar manner as diazepam. Dock score of diazepam and tested compounds were also comparable. All the synthesized molecules were characterized by IR, 1H-NMR and Mass spectrometric data. Elevated plus maze test and Maximal electroshock methods were selected to evaluate antianxiety and anticonvulsant activity respectively. Substitution of methoxy, ethoxy and dimethyl amino groups on benzylidene benzene found to have much therapeutic value but halogen and nitro substitution were not active even unable to show interaction forces with target receptor. Isopropyl group also found to possess potential effect on CNS.