ABSTRACT
Mefenamic acid (MFA) and Nicotinamide (NIC) cocrystal formation in co-milling treatment was investigated by x-ray powder diffractometry (XRPD). Two polymorphic form of Mefenamic acid (MFA form I and MFA form II) were used to form a cocrystal with nicotinamide. Co-milling treatment was carried out at room temperature in a 1:2 molar ratio of MFA and NIC for various times up to 60 min. Samples were analyzed by XRPD. The XRPD showed that MFA form I and MFA form II formed cocrystal with NIC in the same diffractograms pattern. There was no intermediate amorphous form during milling process. The cocrystal formation mechanism was predicted via intermediate eutectic mixtures. The cocrystal formation from MFA form II (15 min) was faster than from MFA form I (45 min) which may explained by variations unit cell dimensions of MFA form I and MFA form II and also the polymorphic transformation of MFA form I.
ABSTRACT
The objective of this study was to develop and validate of Structure-Based Virtual Screening (SBVS) protocol which was used to select the best pose of inhibitor-aspartic protease complex interaction in the active sites of HIV-1 protease, plasmepsin I, II, and IV. Retrospective validation was performed on enhanced dataset of ligands and decoys (DUD-E) for HIV-1 protease. The crystal structures 1XL2, 3QS1, 1SME, and 1LS5 were obtained from Protein Data Bank. The protocol was then challenged to re-dock the ligands to its origin places in the active sites by correlating Tanimoto coefficient (Tc) and binding affinity (Ei) with Root Mean Square Deviation (RMSD). Enrichment factor at 1% false positives (EF1%) values for Tc and Ei were 18.26 and 9.03, respectively, while the Area Under Curve (AUC) values for Tc and Ei were 76.84 and 60.95. The SBVS protocol was valid and showed better virtual screening qualities in ligand identification for HIV-1 protease compared to the original protocol accompanying the release of DUD-E and showed its ability to reproduce the co-crystal pose in the HIV-1 protease, plasmepsin I, II, and IV to its origin places in the active sites.
ABSTRACT
Xanthorrhizol (XNT) is one of major compounds from temulawak`s rhizome and its activity in several cancer cells is known. The aim of this study was to identify mechanism of xanthorrhizol from temulawak`s rhizome as an hERα inhibitor against breast cancer human cell lines. The cytotoxicity of XNT from temulawak`s rhizome on T47D human breast cancer cells lined by sulforhodamine B (SRB) method has been carried out, while molecular docking simulation and pharmacophore modelling methods were employed to predict mechanism of xanthorrhizol as hER inhibitor. Cytotoxicity studies showed that XNT of the isolated and standard had an IC50 100 and 55.50 μg/mL in T47D cells, respectively. Subsequently, molecular docking interaction showed that XNT might be able to compete with estradiol (E2) as a potential ERα inhibitor with the calculated binding free-energy of -8.2 kcal/mol, even the compound superimposed with tamoxifen (4-OHT). XNT formed hydrogen bonds with Arg394 and Glu353 as mention E2 and tamoxifen also formed same interaction with same residue and interacted hydrophobic bonds similar to 4-OHT with: Leu387, Leu384, Leu391, Phe404, L349, Leu346, Met388, and Leu525 of estrogen alpha Ligan Binding Domain (LBD), although 4-OHT indicated stronger hydrophobic when the tail of tamoxifen interacted with Tyr347, Asp351, Trp383 and Leu428. XNT missed two chemical features into HipHop models pharmacophore thus may result in reduced inhibitory activity against T47D compared than 4-OHT. The xanthorrhizol mechanism as a hER inhibitor is postulated as partial estrogen antagonist, is justifiable based on its competitive characteristic versus tamoxifen (OHT-200) which was located on the active side of HER-α.