Environmental toxicants, such as cadmium and bisphenol A (BPA) are endocrine disruptors. In utero, perinatal, or neonatal exposure of BPA to rats affect the male reproductive function, such as the...

The blood-testis barrier (BTB) is a unique ultrastructure in the mammalian testis. Unlike other blood-tissue barriers, such as the blood-brain barrier and the blood-ocular (or blood-retina) barrie...

Background: Entry of HIV-1 into human lymphoid requires activities of viral envelope glycoproteins gp120 and gp41, and two host-cell proteins, the primary receptor CD4 and a chemokine co-receptor. In addition, a third cell-surface protein called protein disulfide isomerase (PDI) is found to play a major role in HIV-1 entry. PDI is capable of mediating thio-disulfide interchange reactions and could enable the reduction of gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. In this scenario, inhibition of HIV-1 entry can be brought about by introducing agents that can block thiol-disulfide interchange reaction of cell surface PDI. There have been studies with agents that inhibit PDI activity, but the exact mode of binding remains to be elucidated; this might provide insights to develop new drugs to target PDI. This study attempts to perceive the mode of binding of dithionitrobenzoic acid (DTNB), and its structurally related compounds on PDI enzyme. Results: We performed molecular docking simulation with six different inhibitors (ligand), which includes DTNB, NSC695265, thionitrobenzoic acid, 2-nitro-5-thiocyanobenzoic acid, 2-nitro-5-sulfo-sulfonyl-benzoic acid and NSC517871 into the redox-active site [C37-G38-H39-C40] of the PDI enzyme and the activity was inferred by redox inhibitory models. All ligands showed favorable interactions and most of them seemed to bind to hydrophobic amino acids Ala34, Trp36, Cys37, Cys40, His39, Thr68 and Phe80. The redox inhibitory conformations were energetically and statistically favored and supported the evidence from wet laboratory experiments reported in the literature. Conclusion: We demonstrated that in silico docking experiment can be effectively carried out to recognize the redox inhibitory models of PDI with inhibitor molecules. Interestingly we found that number of docked clusters with each ligand varies in the range of five to eight and conveys that the binding specificity of each inhibitor varies for PDI. We also identified that Cys37 of the enzyme plays an important role in hydrogen bonding with inhibitors. This residue can be considered to being an active site for anti-HIV drug design. Therefore, by inhibiting PDI, one can, not only prevent the viral entry but also circumvent the problem of viral resistance

Prostate cancer, the second most common form of cancer in adult males is generally treated using hormone therapy but the emergence of hormone refractory prostate cancer poses serious challenges to the existing therapeutic strategies. However, protein kinases are now currently identified as potent targets for treating cancer, and MARK4L, a Ser/Thr kinase in the Par-1 family, is one such kinase that is expressed primarily in the testis and is involved in the regulation of spermatid polarity during spermatogenesis. It is also associated with Wnt-induced prostate carcinogenesis, making it a promising target for the development of anti-cancer therapeutics as part of alternative therapies to counter prostate cancer. In the present work, we predicted the three dimensional structure for the kinase domain of MARK4 and analyzed its structural properties. The results illuminate the presence of the unusual DFG Asp-in/αC helix-out conformation along with the absence of an additional hydrophobic pocket adjacent to the ATP binding site in its inactive state. These structural features accentuate the need for new specific therapeutics against MARK4. Hence, a robust ligand-based pharmacophore model AARRR.9 was developed based on the three dimensional chemical features of 9-oxo-9H-acridin-10-yl derivatives which possess a high specificity towards MARK kinases. A pharmacophore based search identified six potent compounds with a better specificity and binding efficiency to MARK4 bearing stable interactions with key residues K88, A138, D199 and E106, thereby making them tough ATP competitors. The closure of the catalytic cleft observed in the ligand bound complexes and its independency to the movement of the T-loop makes them promising candidates in hampering the role of MARK4 in prostate cancer.