The novel coronavirus (SARS-CoV-2) has infected several million people and caused thousands of deaths worldwide since December 2019. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. Therefore, in this context, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro, and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a database of ∼4600 natural compounds, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including three natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit a large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals interaction. We also found that Glu166 forms H-bonds to all of the inhibitors. Replacing Glu166 by an alanine residue leads to ∼2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potential drugs inhibiting SARS-CoV-2.

We use large-scale molecular dynamics simulations to investigate the phase transformation of aqueous solutions of electrolytes cooled at the critical rate to avoid the crystallization of ice. Homogeneous liquid solutions with up to 20% moles of ions demix on cooling producing nanophase segregated glasses with characteristic dimensions of phase segregation of about 5 nm. The immiscibility is driven by the transformation of water to form a four-coordinated low-density liquid (LDL) as it crosses the liquid-liquid transformation temperature T(LL) of the solution. The ions cannot be incorporated into the tetrahedral LDL network and are expelled to form a solute-rich water nanophase. The simulations quantitatively reproduce the relative amounts of low and high-density liquid water as a function of solute content in LiCl glasses [Suzuki and Mishima, Phys. Rev. Lett. 2000, 85, 1322-1325] and provide direct evidence of segregation in aqueous glasses and their dimensions of phase segregation.

Natural products, including organisms (plants, animals, or microorganisms) have been shown to possess health benefits for animals and humans. According to the estimation of the World Health Organization, in developing countries, 80% of the population has still depended on traditional medicines or folk medicines which are mostly prepared from the plant for prevention or treatment diseases. Traditional medicine from plant extracts has proved to be more affordable, clinically effective and relatively less adverse effects than modern drugs. Literature shows that the attention on the application of phytochemical constituents of medicinal plants in the pharmaceutical industry has increased significantly. Plant-derived secondary metabolites are small molecules or macromolecules biosynthesized in plants including steroids, alkaloids, phenolic, lignans, carbohydrates and glycosides, etc. that possess a diversity of biological properties beneficial to humans, such as their antiallergic, anticancer, antimicrobial, anti-inflammatory, antidiabetic and antioxidant activities Diabetes mellitus is a chronic disease result of metabolic disorders in pancreas β-cells that have hyperglycemia. Hyperglycemia can be caused by a deficiency of insulin production by pancreatic (Type 1 diabetes mellitus) or insufficiency of insulin production in the face of insulin resistance (Type 2 diabetes mellitus). The current medications of diabetes mellitus focus on controlling and lowering blood glucose levels in the vessel to a normal level. However, most modern drugs have many side effects causing some serious medical problems during a period of treating. Therefore, traditional medicines have been used for a long time and play an important role as alternative medicines. Moreover, during the past few years, some of the new bioactive drugs isolated from plants showed antidiabetic activity with more efficacy than oral hypoglycemic agents used in clinical therapy. Traditional medicine performed a good clinical practice and is showing a bright future in the therapy of diabetes mellitus. World Health Organization has pointed out this prevention of diabetes and its complications is not only a major challenge for the future, but essential if health for all is to be attained. Therefore, this paper briefly reviews active compounds, and pharmacological effects of some popular plants which have been widely used in diabetic treatment. Morphological data from V-herb database of each species was also included for plant identification.

Conventional de novo drug design is time consuming, laborious, and resource intensive. In recent years, emerging in silico approaches have been proven to be critical to accelerate the process of bringing drugs to market. Molecular dynamics (MD) simulations of single molecule and molecular complexes have been commonly applied to achieve accurate binding modes and binding energies of drug-receptor interactions. A derivative of MD, namely, steered molecular dynamics (SMD), has been demonstrated as a promising tool for rational drug design. In this paper, we review various studies over the last 20 years using SMD simulations, thus paving the way to determine the relationship between protein structure and function. In addition, the paper highlights the use of SMD simulation for in silico drug design. We also aim to establish an understanding on the key interactions which play a crucial role in the stabilization of peptide-ligand interfaces, the binding and unbinding mechanism of the ligand-protein complex, the mechanism of ligand translocating via membrane, and the ranking of different ligands on receptors as therapeutic candidates.

Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid mutation of the flu virus. Unfortunately, how mutations actually confer drug resistance is not well understood. In this study, we employ molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, as well as graphics processing unit (GPU)-accelerated electrostatic mapping, to uncover the mechanism behind point mutation induced oseltamivir-resistance in both H5N1 “avian” and H1N1pdm “swine” flu N1-subtype neuraminidases. The simulations reveal an electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase. The binding pathway for oseltamivir suggests how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms.