No abstract

Blood coagulation is a cascade of complex enzymatic reactions which involves specific proteins and cellular components to interact and prevent blood loss. The coagulation process begins by either “Tissue Dependent Pathway” (also known as extrinsic pathway) or by “contact activation pathway” (also known as intrinsic pathway). TFPI is an endogenous multivalent Kunitz type protease inhibitor which inhibits Tissue factor dependent pathway by inhibiting Tissue Factor:Factor VIIa (TF:FVIIa) complex and Factor Xa. TFPI is one of the most studied coagulation pathway inhibitor which has various clinical and potential therapeutic applications, however, its exact mechanism of inhibition is still unknown. Structure based mechanism elucidation is commonly employed technique in such cases. Therefore, in the current study the generated a complete TFPI structural model so as to understand the mechanistic details of it's functioning. The model was checked for stereochemical quality by PROCHECK-NMR, WHATIF, ProSA, and QMEAN servers. The model was selected, energy minimized and simulated for 1.5ns. The result of the study may be a guiding point for further investigations on TFPI and its role in coagulation mechanism.

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β-Cyclodextrin (β-CD) is the potential drug carrier to deliver antitumor drugs like doxorubicin (DOX). However, the mechanism for the inclusion complex formation is still unclear and needs to be explored. This study investigated the effect of pH on the inclusion of DOX into thiolated β-CD (β-CD-SH) by electrochemical and molecular dynamics (MD) simulation. The electrochemical study shows a clear difference at different pH values. The redox peak due to the DOX is strongly influenced by pH. At neutral pH, the peak intensity decreases with time, while slight variation is observed at acidic and basic pH, depicting the association of DOX to the β-CD-SH cavity at neutral pH. Also, due to the association, the charge transfer resistance variation increased with time at neutral pH and decreased at basic and acidic pH. The electrochemical study was further supported by MD simulation, suggesting that the cyclodextrin (CD) ring gets slightly elongated due to the flipping of glucose units, specifically at neutral pH leading to a strong association. Also, another significant result observed that the DOX forms an inclusion complex with β-CD-SH in quinol conformation, not in quinone. Briefly, the study provides the necessary molecular binding information for designing an effective β-CD-based targeted drug delivery system.

Metalloproteins are well-known for playing various physicochemical processes in all life forms, including viruses. Some life-threatening viruses (such as some members of the coronaviridae family of viruses) are emerged and remerged frequently and are rapidly transmitted throughout the globe. This study aims to identify and characterize the metal-binding proteins of the coronaviridae family of viruses and further provides insight into the metal-binding protein's role in sustaining and propagating viruses inside a host cell and in the outer environment. In the present study, the available proteome of the coronaviridae family was exploited. Identified potential metal-binding proteins were analyzed for their functional domains, structural aspects, and sub-cellular localization. We also demonstrate phylogenetic aspects of all predicted metal-binding proteins among other coronaviridae family members to understand the evolutionary trend among their respective hosts. A total of 256 proteins from 51 different species of coronaviruses are predicted as metal-binding proteins. These metal-binding proteins perform various key roles in the replication and survival of viruses within the host cell. Cysteine, aspartic acid, threonine, and glutamine are key amino acid residues interacting with respective metal ions. Our observations also indicate that the metalloproteins of this family of viruses circulated and evolved in different hosts, which supports the zoonotic nature of coronaviruses. The comprehensive information on metal-binding proteins of the coronaviridae family may be further helpful in designing novel therapeutic metalloprotein targets. Moreover, the study of viral metal-binding proteins can also help to understand the roles of metal-binding proteins in virus pathogenesis and virus-host interactions.