The Dengue virus M protein is a 75 amino acid polypeptide with two helical transmembranes (TM). The TM domain oligomerizes to form an ion channel, facilitating viral release from the host cells. The M protein has a critical role in the virus entry and life cycle, making it a potent drug target. The oligomerization of the monomeric protein was studied using ab initio modeling and molecular dynamics (MD) simulation in an implicit membrane environment. The representative structures obtained showed pentamer as the most stable oligomeric state, resembling an ion channel. Glutamic acid, threonine, serine, tryptophan, alanine, isoleucine form the pore-lining residues of the pentameric channel, conferring an overall negative charge to the channel with approximate length of 51.9 Å. Residue interaction analysis (RIN) for M protein shows that Ala94, Leu95, Ser112, Glu124, and Phe155 are the central hub residues representing the physicochemical interactions between domains. The virtual screening with 165 different ion channel inhibitors from the ion channel library shows monovalent ion channel blockers, namely lumacaftor, glipizide, gliquidone, glisoxepide, and azelnidipine to be the inhibitors with high docking scores. Understanding the three-dimensional structure of M protein will help design therapeutics and vaccines for Dengue infection.

P7 is the only viral channel encoded by the Hepatitis C Virus (HCV) genome. It is a small, highly hydrophobic protein containing 63 amino acids. Structural studies have shown that p7 has two transmembrane (TM) α helices linked by a short dibasic cytoplasmic loop. P7, mostly placed in the endoplasmic reticulum (ER), is a membrane-associated protein. The results obtained from different studies revealed that p7 is a polytopic membrane protein that could oligomerize in membrane bilayer to create ion channels with cation selectivity. In addition, p7 is highly conserved and plays an important role in the assembly and release of mature viral particles. Thus, it can be considered as a potential target for anti-HCV drugs. It has been found that several compounds (amantadine, rimantadine, hexamethylene amiloride (HMA) and long-alkyl-chain iminosugar (IS) derivatives) inhibit p7 channel ability. Another new inhibitor identified as BIT225, a derivative of amiloride, also inhibits the viroporin function of HIV-1 Vpu and HCV p7. In the present study, molecular dynamics simulations were applied to get insights into molecular details of a BIT225 binding site. In addition, the g_mmpbsa approach was employed to calculate the binding free energy and free energy decomposition per residue. MD simulation results in the p7-BIT225 complex revealed that drug binding to hydrophobic pocket can allosterically inhibit ion conduction via the funnel tip by restricting significant intrinsic channel breath at the tip of the funnel. Based on the molecular dynamics simulation (MD) analysis and the energy profiles, the hydrophobic interactions were the main driving force for BIT225 binding.