The gonadotropin known as follicle-stimulating hormone (FSH) plays a key role in regulating reproductive processes. Physiologically active FSH is a glycoprotein that can accommodate glycans on up to four asparagine residues, including two sites in the FSHα subunit that are critical for biochemical function, plus two sites in the β subunit, whose differential glycosylation states appear to correspond to physiologically distinct functions. Some degree of FSHβ hypo-glycosylation seems to confer advantages toward reproductive fertility of child-bearing females. In order to identify possible mechanistic underpinnings for this physiological difference we have pursued computationally intensive molecular dynamics simulations on complexes between the high affinity site of the gonadal FSH receptor (FSHR) and several FSH glycoforms including fully-glycosylated (FSH²⁴), hypo-glycosylated (e.g., FSH¹⁵), and completely deglycosylated FSH (dgFSH). These simulations suggest that deviations in FSH/FSHR binding profile as a function of glycosylation state are modest when FSH is adorned with only small glycans, such as single N-acetylglucosamine residues. However, substantial qualitative differences emerge between FSH¹⁵ and FSH²⁴ when FSH is decorated with a much larger, tetra-antennary glycan. Specifically, the FSHR complex with hypo-glycosylated FSH¹⁵ is observed to undergo a significant conformational shift after 5–10 ns of simulation, indicating that FSH¹⁵ has greater conformational flexibility than FSH²⁴ which may explain the more favorable FSH¹⁵ kinetic profile. FSH¹⁵ also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

HIV-1 protease (HIV-pr) acts as the most promising drug target commonly used for anti-HIV therapy. However, the efficiency of the protease inhibitors (PIs) has been greatly reduced by mutations assisted drug resistance. Because of the richness and greatest diversity of plants, the current study aims at exploring phytocompounds as PIs with potential inhibitory properties against HIV-pr through multi-faceted in silico tactics. Virtually screened phytocompounds (Epicatechin, Epigallocatechol, D-Catechin, Afrormosin and Afzelechin) were employed via docking to the WT and I50V mutant. Molecular dynamics of complexed HIV-pr with 50 ns trajectory expose that the nominated phytocompounds can efficiently bind to the HIV-pr active site and control the flap dynamics. The relative binding free energies for the five phytocompounds to both WT and I50V mutant were calculated by MM-GBSA method. The increased binding affinity was witnessed for most of the PIs (except AFZ), and on account of the robust binding, which may be primarily accredited due to the upsurge in ΔE_ele and ΔE_vdw, the I50V mutant might be well acclimatised by the PIs. Overall, this study led to the identification of potential hit compounds like Epigallocatechol with favourable pharmacokinetic properties for both WT and I50 V may lead to the discovery of robust new drugs against HIV-pr.

SARS-CoV-2 M^pro is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 M^pro. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M^pro, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 M^pro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 M^pro by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (ΔG_Bind = −28.31 kcal/mol) due to an increased favorable van der Waals (ΔE_vdw) interactions and decreased solvation (ΔG_solv) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (−6.85 kcal/mol), KNI-227 (−18.36 kcal/mol), KNI-272 (−15.69 kcal/mol) and KNI-1931 (−21.59 kcal/mol) against SARS-CoV-2 M^pro. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 M^pro drugs. Communicated by Ramaswamy H. Sarma