Accurate prediction of absolute protein−ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor− ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC 50 = 0.87 nM, ∼2000-fold improvement in potency) with cocrystal confirmation.

Alzheimer's disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a superenzyme family responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently, PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have exhibited remarkable cognitive improvement effects in preclinical studies and over 15 of them have been subjected to clinical trials. The aim of this review is to summarize the outstanding progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms, and limitations of these PDE inhibitors in the treatment of AD are also reviewed and discussed.

The outbreak of coronavirus disease 2019 (COVID‐19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, has become a global crisis. As of November 9, COVID‐19 has already spread to more than 190 countries with 50,000,000 infections and 1,250,000 deaths. Effective therapeutics and drugs are in high demand. The structure of SARS‐CoV‐2 is highly conserved with those of SARS‐CoV and Middle East respiratory syndrome‐CoV. Enzymes, including RdRp, Mpro/3CLpro, and PLpro, which play important roles in viral transcription and replication, have been regarded as key targets for therapies against coronaviruses, including SARS‐CoV‐2. The identification of readily available drugs for repositioning in COVID‐19 therapy is a relatively rapid approach for clinical treatment, and a series of approved or candidate drugs have been proven to be efficient against COVID‐19 in preclinical or clinical studies. This review summarizes recent progress in the development of drugs against SARS‐CoV‐2 and the targets involved.

Pyridoxal-5′-phosphate (PLP), the active form of vitamin B 6 , is an important and versatile coenzyme involved in a variety of enzymatic reactions, accounting for about 4% of all classified activities. However, the detailed catalytic reaction pathways for PLP-dependent enzymes remain to be explored. Methionine-γ-lyase (MGL), a promising alternative anti-tumor agent to conventional chemotherapies whose catalytic mechanism is highly desired for guiding further development of re-engineered enzymes, was used as a representative PLP-dependent enzyme, and the catalytic mechanism for L-Met elimination by MGL was explored at the first-principles quantum mechanical/molecular mechanical (QM/MM) level with umbrella sampling. The QM/MM calculations revealed that the enzymatic reaction pathway consists of 4 stages for a total of 19 reaction steps with five intermediates captured in available crystal structures. Furthermore, the more comprehensive role of PLP was revealed. Besides the commonly known role of "electron sink", coenzyme PLP can also assist proton transfer and temporarily store the excess proton generated in some intermediate states by using its hydroxyl group and phosphate group. Thus, PLP is participated in most of the 19 steps. This study not only provided a theoretical basis for further development and re-engineering MGL as a potential anti-tumor agent, but also revealed the comprehensive role of PLP which could be used to explore the mechanisms of other PLPdependent enzymes.