Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein-ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery. Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets. Expert opinion: MD simulations have been used widely in investigating the pathogenic mechanisms of diseases caused by protein misfolding, in virtual screening, and in investigating drug resistance mechanisms caused by mutations of the target. These issues are very difficult to solve by experimental methods alone. Thus, in the future, MD simulations will have wider application with the further improvement of computational capacity and the development of better sampling methods and more accurate force fields together with more efficient analysis methods.

Nine new monoterpenoid indole alkaloids, ervatamines A-I (1-9), and five known ones (10-14), were isolated from Ervatamia hainanensis. The new structures were elucidated by extensive spectroscopic analysis and comparison to known compounds. Their absolute configurations were determined by various methods including computational methods, X-ray diffraction analysis, and electronic circular dichroism spectroscopy, as well as chemical transformations. Ervatamine A (1) is a ring-C-contracted ibogan-type monoterpenoid indole alkaloid with an unusual 6/5/6/6/6 pentacyclic rearranged ring system. Ervatamines B-E (2-5) display a nitrogen-containing 9/6 ring system, which is rarely observed in nature. The epimeric ervatamines B (2) and C (3) possess a 22-nor-monoterpenoid indole alkaloid carbon skeleton, which was only found in deformylstemmadenine. Compounds 10 and 14 exhibited significant anti-inflammatory activities, with IC50 values of 25.5 and 41.5 μM, respectively, while the IC50 value of indomethacin as a positive control was found to be 42.6 μM. Additionally, compound 9 showed mild activity against 786-O and HL-60 cell lines.

The microtubule-associated protein tau is critical for the development and maintenance of the nervous system. Tau dysfunction is associated with a variety of neurodegenerative diseases called tauopathies, which are characterized by neurofibrillary tangles formed by abnormally aggregated tau protein. Studying the aggregation mechanism of tau protein is of great significance for elucidating the etiology of tauopathies. The hexapeptide 306VQIVYK311 (PHF6) of R3 has been shown to play a vital role in promoting tau aggregation. In this study, long-term all-atom molecular dynamics simulations in explicit solvent were performed to investigate the mechanisms of spontaneous aggregation and template-induced misfolding of PHF6, and the dimerization at the early stage of nucleation was further specifically analyzed by the Markov state model (MSM). Our results show that PHF6 can spontaneously aggregate to form multimers enriched with β-sheet structure and the β-sheets in multimers prefer to exist in a parallel way. It is observed that PHF6 monomer can be induced to form a β-sheet structure on either side of the template but in a different way. In detail, the β-sheet structure is easier to form on the left side but does not extend well, but on the right side, the monomer can form the extended β-sheet structure. Furthermore, MSM analysis shows that the formation of dimer mainly occurs in three steps. First, the separated monomers collide with each other at random orientations, and then a dimer with short β-sheet structure at the N-terminal forms; finally, β-sheets elongate to form an extended parallel β-sheet dimer. During these processes, multiple intermediate states are identified and multiple paths can form a parallel β-sheet dimer from the disordered coil structure. Moreover, the residues I308, V309, and Y310 play an essential role in the dimerization. In a word, our results uncover the aggregation and misfolding mechanism of PHF6 from the atomic level, which can provide useful theoretical guidance for rational design of effective therapeutic drugs against tauopathies.

Recently, small-molecule compounds have been reported to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1. All these inhibitors had a common scaffold and interacted with the cavity formed by two PD-L1 monomers. This special interactive mode provided clues for the structure-based drug design, however, also showed limitations for the discovery of small-molecule inhibitors with new scaffolds. In this study, we revealed the structure-activity relationship of the current small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. During the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to have a more stable binding mode with one PD-L1 monomer than the other and the small-molecule inducing PD-L1 dimerization was further stabilized by the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on both monomers and the water bridges involved in ALys124. The unbinding process prediction showed that the PD-L1 dimerization kept stable upon the dissociation of ligands. It's indicated that the formation and stability of the small-molecule inducing PD-L1 dimerization was the key factor for the inhibitory activities of these ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities by structural modifications. Taken together, the results in this study could guide the structural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.