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Background: Lack of effective early-stage HIV-1 inhibitor instigated the need for screening of novel gp120-CD4 binding inhibitor. Polyphenols, a secondary metabolite derived from natural sources are reported to have broad spectrum HIV-1 inhibitory activity. However, the gp120-CD4 binding inhibitory activity of polyphenols has not been analysed in silico yet. Objectives: To establish the usage of phytopolyphenols (Theaflavin, Epigallocatechin (EGCG), Ellagic acid and Gallic acid) as early stage HIV-1 inhibitor by investigating their binding mode in reported homology of gp120-CD4 receptor complex using in silico screening studies and in vitro cell line studies. Methods: The in silico molecular docking and molecular simulation studies were performed using Schrödinger 2013-2 suite installed on Fujitsu Celsius Workstation. The in vitro cell line studies were performed in the TZM-bl cell line using MTT assay and β-galactosidase assay. Results: The results of molecular docking indicated that Theaflavin and EGCG exhibited high XP dock score with binding pose exhibiting Van der Waals interaction and hydrophobic interaction at the deeper site in the Phe43 cavity with Asp368 and Trp427. Both Theaflavin and EGCG form a stable complex with the prepared HIV-1 receptor and their binding mode interaction is within the vicinity 4 Å. Further, in vitro cell line studies also confirmed that Theaflavin (SI = 252) and EGCG (SI = 138) exert better HIV-1 inhibitory activity as compared to Ellagic acid (SI = 30) and Gallic acid (SI = 34). Conclusions: The results elucidate a possible binding mode of phytopolyphenols, which pinpoints their plausible mechanism and directs their usage as early stage HIV-1 inhibitor.

The research envisioned was the development of diltiazem hydrochloride effervescent floating matrix tablet using a risk-based approach. Preliminarily, the in vitro drug release profile was derived which theoretically simulated the in vivo condition after oral administration. Considering this as a rationale, the formulation development was initiated with defining the quality target product profile (QTPP) and critical quality attributes (CQAs). The preliminary studies were conducted to screen material attributes and process parameters followed by their risk assessment studies to select the plausible factors affecting the drug product CQAs, i.e., floating lag time and drug release profile. A 3(2) full factorial design was used to estimate the effect of the amount of swelling polymer (X 1) and gas-generating agent (X 2) on percent drug release (Q t1h and Q t8h) and floating lag time. Response and interaction plots were generated to examine the variables. Selection of an optimized formulation was done using desirability function and further validated. The model diagnostic plots represent the absence of outliers. The optimized formula obtained by the software was further validated, and the result of drug release and floating lag time was close to the predicted values. In a clear and concise way, the current investigations report the successful development of an effervescent floating matrix tablet for twice daily administration of diltiazem hydrochloride.