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Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A number of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease associations.

Structure‐based drug design has been an integral part of drug discovery for over three decades, contributing to the development of numerous approved drugs. Here we discuss the evolution, as well as the current state, of structure‐based drug design within the pharmaceutical industry, using data from AstraZeneca's internal repository for crystal structures to provide additional context. Over the past 20 years, the company has transitioned from a mixed in‐house and synchrotron data collection model to a `synchrotron‐only' approach, enabled by technological advancements at synchrotron facilities. We provide real‐world examples of structure delivery to projects, including a high‐throughput project and a case where a single structure was pivotal for discovering a candidate drug. We conclude that, despite recent developments in single‐particle cryo‐EM and deep‐learning structure prediction methods, macromolecular crystallography remains a critical tool for drug discovery. Structure‐based drug design has been a critical component of drug discovery for over 30 years, contributing to numerous approved drugs. The paper discusses the approach taken by AstraZeneca (Sweden) to synchrotron data collection for supporting a large portfolio of drug discovery projects and provides examples to demonstrate the continued importance of experimental structures.

Cyclic peptoids have recently emerged as an important class of bioactive scaffolds with unique conformational properties and excellent metabolic stabilities. In this paper, we describe the design and synthesis of novel cyclic octamer peptoids as simplified isosters of mycotoxin depsipeptides bassianolide, verticilide A1, PF1022A and PF1022B. We also examine their complexing abilities in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt and explore their general insecticidal activity. Finally, we discuss the possible relationship between structural features of free and Na+-complexed cyclic octamer peptoids and bioactivities in light of conformational isomerism, a crucial factor affecting cyclic peptoids’ biomimetic potentials.

Introduction The development of a human immunodeficiency virus 1 (HIV‐1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly neutralizing antibodies (bNAbs), which likely involves the use of native‐like HIV‐1 envelope (Env) trimers at some or all stages of vaccination. Development of such trimers has been very difficult, but much progress has been made in the past decade, starting with the BG505 SOSIP trimer, elucidation of its atomic structure and implementing subsequent design iterations. This progress facilitated understanding the weaknesses of the Env trimer, fuelled structure‐guided HIV‐1 vaccine design and assisted in the development of new vaccine designs. This review summarizes the relevant literature focusing on studies using structural biology to reveal and define HIV‐1 Env sites of vulnerability; to improve Env trimers, by creating more stable versions; understanding antibody responses in preclinical vaccination studies at the atomic level; understanding the glycan shield; and to improve “on‐target” antibody responses versus “off‐target” responses. Methods The authors conducted a narrative review of recently published articles that made a major contribution to HIV‐1 structural biology and vaccine design efforts between the years 2000 and 2021. Discussion The field of structural biology is evolving at an unprecedented pace, where cryo‐electron microscopy (cryo‐EM) and X‐ray crystallography provide complementary information. Resolving protein structures is necessary for defining which Env surfaces are accessible for the immune system and can be targeted by neutralizing antibodies. Recently developed techniques, such as electron microscopy‐based polyclonal epitope mapping (EMPEM) are revolutionizing the way we are analysing immune responses and shed light on the immunodominant targets on new vaccine immunogens. Such information accelerates iterative vaccine design; for example, by reducing undesirable off‐target responses, while improving immunogens to drive the more desirable on‐target responses. Conclusions Resolving high‐resolution structures of the HIV‐1 Env trimer was instrumental in understanding and improving recombinant HIV‐1 Env trimers that mimic the structure of viral HIV‐1 Env spikes. Newly emerging techniques in structural biology are aiding vaccine design efforts and improving immunogens. The role of structural biology in HIV‐1 vaccine design has indeed become very prominent and is unlikely to diminish any time soon.

Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adults. High levels of neutralizing antibodies, mostly directed against the viral fusion (F) glycoprotein, correlate with protection against either hRSV or hMPV. However, no cross‐neutralization is observed in polyclonal antibody responses raised after virus infection or immunization with purified F proteins. Based on crystal structures of hRSV F and hMPV F, we designed chimeric F proteins in which certain residues of well‐characterized antigenic sites were swapped between the two antigens. The antigenic changes were monitored by ELISA with virus‐specific monoclonal antibodies. Inoculation of mice with these chimeras induced polyclonal cross‐neutralizing antibody responses, and mice were protected against challenge with the virus used for grafting of the heterologous antigenic site. These results provide a proof of principle for chimeric fusion proteins as single immunogens that can induce cross‐neutralizing antibody and protective responses against more than one human pneumovirus. Synopsis Chimeric fusion (F) proteins bearing neutralizing epitopes of hRSV and hMPV offer the possibility of using a single immunogen to induce cross‐protective antibody responses against both viruses. Postfusion‐stabilized hMPV F bearing antigenic site II of hRSV induced antibodies that neutralized hRSV and hMPV and protected against an hRSV challenge. Prefusion‐stabilized hRSV F bearing antigenic site IV of hMPV also induced antibodies that cross‐neutralized hRSV and hMPV. Graphical Abstract Chimeric fusion (F) proteins bearing neutralizing epitopes of hRSV and hMPV offer the possibility of using a single immunogen to induce cross‐protective antibody responses against both viruses.

Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand‐binding sites in tubulin makes this protein an attractive target for anti‐parasite drug discovery. However, despite remarkable successes as anti‐cancer agents, the rational development of protozoan parasite‐specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug‐binding sites. Based on this information, we rationally designed the parasite‐specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species‐specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much‐needed, novel parasite inhibitors. Synopsis In an effort to discover novel drug‐scaffolds targeting unique parasite proteins and pathways, specific inhibition of parasite tubulin was achieved using structure‐guided rational drug design. The atomic architecture of apicomplexan tubulin‐drug binding sites was resolved. Species‐specific tubulin binding drugs were studied. A parasite tubulin inhibitor dubbed parabulin was designed. Graphical Abstract In an effort to discover novel drug‐scaffolds targeting unique parasite proteins and pathways, specific inhibition of parasite tubulin was achieved using structure‐guided rational drug design.

Recent remarkable advancements in geometric deep generative models, coupled with accumulated structural data, enable structure‐based drug design (SBDD) using only target protein information. However, existing models often struggle to balance multiple objectives, excelling only in specific tasks. BInD, a diffusion model with knowledge‐based guidance, is introduced to address this limitation by co‐generating molecules and their interactions with a target protein. This approach ensures balanced consideration of key objectives, including target‐specific interactions, molecular properties, and local geometry. Comprehensive evaluations demonstrate that BInD achieves robust performance across all objectives, matching or surpassing state‐of‐the‐art methods. Additionally, an NCI‐driven molecule design and optimization method is proposed, enabling the enhancement of target binding and specificity by elaborating the adequate interaction patterns. Can a generative model design molecules that truly understand their targets? BInD, a diffusion‐based framework, co‐generates 3D molecules and their interactions with proteins by learning target‐specific interacting patterns. With knowledge‐based guidance and NCI‐driven optimization, BInD balances affinity, geometry, and drug‐likeness – pushing the boundary of multi‐objective molecular design in structure‐based drug discovery.

A structure-based lead optimization procedure is an essential step to finding appropriate ligand molecules binding to a target protein structure in order to identify drug candidates. This procedure takes a known structure of a protein-ligand complex as input, and structurally similar compounds with the query ligand are designed in consideration with all possible combinations of atomic species. This task is, however, computationally hard since such combinatorial optimization problems belong to the non-deterministic nonpolynomial-time hard (NP-hard) class. In this paper, we propose the structure-based lead generation and optimization procedures by a degenerate optical parametric oscillator (DOPO) network. Results of numerical simulation demonstrate that the DOPO network efficiently identifies a set of appropriate ligand molecules according to the Boltzmann sampling law.

The histone deacetylases (HDACs) family plays a critical role in tumorigenesis and has been identified as having a significant impact on tumor immunity. Herein, we employed a fragment‐centric structure‐based design platform, leading to the discovery of SDFZ‐8 as a highly potent HDAC1 inhibitor (IC50 = 0.4 nM). SDFZ‐8 exhibits strong antiproliferative effects by enabling histone acetylation and inducing cell apoptosis. Crucially, SDFZ‐8 treatment led to a significant enhancement of antitumor immunity, as evidenced by increased activation of T cells, enhanced polarization of M1‐type macrophages, improved antigen presentation, and alleviation of the immunosuppressive tumor microenvironment. Specifically, we observed that SDFZ‐8 notably upregulated the expression of PD‐L1 in both tumor cells and tumor‐infiltrating lymphocytes, which is closely associated with its inhibition against HDAC1. Of particular interest, combining SDFZ‐8 with PD‐L1 blockade resulted in a synergistic antitumor effect surpassing that of either monotherapy. Taken together, our findings establish SDFZ‐8 as a novel HDAC1 inhibitor that concurrently targets tumor cells and immune evasion mechanisms, providing a rational combinatorial strategy to enhance cancer immunotherapy efficacy. In this study, we designed a novel quinoline derivative as a potent HDAC inhibitor SDFZ‐8 and assessed its capability to enhance cancer immunotherapy, along with its potential synergistic effects with PD‐L1 blockade.

The binding of amyloid precursor protein (APP) expressed on tumor cells to death receptor 6 (DR6) could initiate the necroptosis pathway, which leads to necroptotic cell death of vascular endothelial cells (ECs) and results in tumor cells (TCs) extravasation and metastasis. This study reports the first inhibitor of DR6/APP interaction as a novel class of anti‐hematogenous metastatic agent. By rationally utilizing three combined strategies including selection based on phage display library, d‐retro‐inverso modification, and multiple conjugation of screened peptidomimetic with 4‐arm PEG, the polymer–peptidomimetic conjugate PEG‐tAHP‐DRI (tetra‐(D‐retro‐inverso isomer of AHP‐12) substitued 4‐arm PEG5k) is obtained as the most promising agent with the strongest binding potency (KD = 51.12 × 10−9 m) and excellent pharmacokinetic properties. Importantly, PEG‐tAHP‐DRI provides efficient protection against TC‐induced ECs necroptosis both in vitro and in vivo. Moreover, this ligand exhibits prominent anti‐hematogenous metastatic activity in serval different metastatic mouse models (B16F10, 4T1, CT26, and spontaneous lung metastasis of 4T1 orthotopic tumor model) and displays no apparent detrimental effects in preliminary safety evaluation. Collectively, this study demonstrates the feasibility of exploiting DR6/APP interaction to regulate hematogenous tumor cells transendothelial migration and provides PEG‐tAHP‐DRI as a novel and promising inhibitor of DR6/APP interaction for developments of anti‐hematogenous metastatic therapies. Binding of amyloid precursor protein (APP) and death receptor 6 (DR6) is shown to initiate the necroptosis pathway and lead to tumor cells metastasis. The combined strategies of selection based on phage display library, d‐retro‐inverso modification, and multiple conjugation result in the development of conjugate PEG‐tAHP‐DRI (tetra‐(D‐retro‐inverso isomer of AHP‐12) substitued 4‐arm PEG5k) that blocks APP‐DR6 interactions and shows promising anti‐hematogenous metastatic activity both in vitro and in vivo.