Recent progress in fragment-based drug discovery facilitated by NMR spectroscopy

Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.

Applications and prospects of cryo-EM in drug discovery

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins

Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.

Development of non-nucleoside reverse transcriptase inhibitors(NNRTIs):our past twenty years

Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last 20 years,our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs,including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine(HEPT),thio-dihydro-alkoxy-benzyl-oxopyrimidine(S-DABO),diaryltriazine(DATA),diarylpyrimidine(DAPY)analogues,and their hybrid derivatives.Application of integrated modern medicinal strategies,including structure-based drug design,fragment-based optimization,scaffold/fragment hopping,molecular/fragment hybridization,and bioisosterism,led to the development of several highly potent analogues for further evaluations.In this paper,we review the development of NNRTIs in the last two decades using the above optimization strategies,including their structure-activity relationships,molecular modeling,and their binding modes with HIV-1 reverse transcriptase(RT).Future directions and perspectives on the design and associated challenges are also discussed.

Theoretical study of low-lying excited states of molecular aggregates. I. Development of linear-scaling TD-DFT

The project aims to develop an integrated linear-scaling time-dependent density functional theory (TD-DFT) for studying low-lying excited states of luminescent molecular materials, especially those fluorescence and phosphorescence co-emitting systems. The central idea will be "from fragments to molecule" (FF2M). That is, the fragmental information will be employed to synthesize the molecular wave function, such that the locality (transferability) of the fragments (functional groups) is directly built into the algorithms. Both relativistic and spin-adapted open-shell TD-DFT will be considered. Use of the renormalized exciton method will also be made to further enhance the efficiency and accuracy of TD-DFT. Solvent effects are to be targeted with the fragment-based solvent model. It is expected that the integrated TD-DFT and program will be of great value in rational design of luminescent molecular materials.