Fragment-based diffusion modeling is an efficient and interpretable strategy for the discovery of computationally prioritized PD-L1 small-molecule candidate inhibitors and offers a promising framework for tackling challenging targets in cancer immunotherapy.
Cyclin-dependent kinase 2 (CDK2) is a crucial regulator of the cell cycle and a promising target for cancer treatment. In this study, five known inhibitors were used to create a receptor-based pharmacophore model that includes an aromatic ring, hydrogen bond donors and acceptors, a negatively charged group, and a hydrophobic region. This model screened the Asinex database and found 1881 hits. Molecular docking narrowed the selection to the 10 best candidates (MD1-MD10), with MD1-MD5 showing strong binding affinities, with docking scores between -11.66 and -10.56 kcal/mol. These five compounds were further tested using ADME/T profiling, DFT calculations, and 100 ns molecular dynamics simulations. Principal component analysis (PCA) and free energy landscape (FEL) evaluations further confirmed stable conformational behavior across the MD simulation trajectories. The HOMO-LUMO gaps suggested stable electronic properties, and the MD simulations confirmed complex stability, with RMSD and RMSF values ranging from 2.0 to 2.8 Å. Overall, MD1-MD5 demonstrated excellent binding, structural stability, and pharmacokinetic properties, making them strong candidates for future CDK2-targeted anticancer research.
Dharmesh A. Patel, Apurva Prajapati, Siddharth S. Patel et al.· Biotechnology and applied bi...· 0 citations
The development of theranostic tools for the early detection and localization of tumors represents a major challenge in oncology. Among emerging strategies, the targeting of Programmed Death Ligand-1 (PD-L1), a key immune checkpoint protein overexpressed in many tumor types, has gained significant attention. In this work, we report design and development of theranostic gold nanostructures functionalized with PD-L1-targeting peptides (PTP, sPTP, and rPTP) whose sequences were identified combining structural analysis of the PD-1/PD-L1 interaction interface and molecular dynamics simulations. This is because the design of functional nanostructures for protein targeting requires a precise understanding of how molecular recognition is affected by ligand organization at interfaces; therefore, peptide design was guided not only by the selection of key residues involved in binding but also by the evaluation of peptide assemblies to explicitly account for the collective effects governing target recognition. Indeed, beyond conventional evaluation of protein/single-peptide interaction, peptide clusters and surface-anchored monolayers were investigated to consider features like peptide assembly, organization, and reduced conformational freedom in the nanostructure/PD-L1 interaction. Results indicate that peptide sequence and orientation critically determine monolayer organization and accessibility of the PD-L1 binding motif. The computational predictions were experimentally validated by synthesizing peptide-functionalized gold nanostructures and evaluating their targeting performance against MDA-MB-231 breast cancer cells over-expressing PD-L1, using the surface-enhanced Raman scattering technique: NS functionalized with PTPs achieved the targeting of approximately 85% of MDA-MB-231 cells at 100 pM nanostructure concentration, compared to 23% for those functionalized with rPTP, demonstrating a nearly four-fold difference attributable exclusively to peptide orientation on the nanostructure surface. The specific system investigated in this work establishes a computational framework for the rational design of peptide-functionalized nanostructures, providing insights into the collective behavior of peptide monolayers and offering a smart methodology that, while demonstrated here for targeting PD-L1, is in principle applicable to other protein targets.
Micaela Giannetti, Marina Gobbo, Lucio Litti et al.· ACS Applied Bio Materials· 0 citations
Chronic inflammation is closely associated with cancer progression through the promotion of angiogenesis and tumor-supportive signaling pathways. Tumor necrosis factor-α–induced protein 8-like 2 (TIPE2) regulates leukocyte polarization through phosphoinositide transport and represents a promising therapeutic target for solid tumors. However, the large hydrophobic cavity of TIPE2 presents a significant challenge for inhibitor design. In this work, a quadrant docking grid system was developed to enable fragment docking in defined regions of the binding cavity, facilitating fragment linking with minimal overlap and maximal spatial coverage. To our knowledge, this is the first application of a quadrant grid docking strategy for fragment-based inhibitor design. Fragments were screened using AutoDock Vina 1.2.3 and selected based on both binding affinity and predicted aqueous solubility. The highest-binding linked compounds, F1-F12 and F1-F13, exhibited binding affinities of −12.4 and −11.5 kcal mol−1, respectively. Rational modifications yielded compounds MF112 and MF113 with improved predicted ADME properties while maintaining strong binding affinities of −11.7 kcal mol−1. Molecular dynamics simulations demonstrated stable binding complexes over 5 ns trajectories, with RMSD stabilization after approximately 1–2 ns. These results demonstrate that quadrant-based fragment docking provides an effective strategy for designing inhibitors targeting proteins with large binding cavities and provides promising lead compounds for the development of TIPE2 inhibitors.
Dorothea West, Pearl Miller, Jerica Wilson et al.· The Scientist· 0 citations
The quaternary ammonium strategy represents an effective approach to developing water-soluble PD-1/PD-L1 inhibitors with dual immunomodulatory and antiangiogenic functions.
Jianwei Xu, Pan Yang, Xixiang Yang et al.· Journal of Medicinal Chemist...· 0 citations
Protein–protein interactions dominated by large, flat interfaces are widely considered challenging drug targets. The programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) immune checkpoint exemplifies this problem, as the interaction is mediated by an extended β-sheet surface lacking deep pockets. Despite this, PD-L1 has been successfully inhibited by chemically distinct modalities, including antibodies, macrocyclic peptides, and small molecules. Here, we present a comparative, structure-driven analysis of PD-L1 complexes deposited in the Protein Data Bank and demonstrate a striking convergence: all effective inhibitors engage the same CC′FG β-sheet face of PD-L1. Antibodies directly occlude this surface, macrocyclic peptides such as pAC65 reproduce antibody-like surface coverage in a compact and preorganized scaffold, and biphenyl small molecules neutralize the same epitope indirectly by inducing PD-L1 homodimerization. This unified structural framework reveals modality-agnostic design principles for targeting flat immune checkpoint PPIs. This Perspective provides a unified structural framework for understanding PD-L1 inhibition across clinically tested antibodies, macrocyclic peptides, and small molecules. Both visualizing and quantitatively comparing interface overlap, hotspot conservation, and buried surface area, the work demonstrates that distinct inhibitory modalities converge on the same functional CC′FG hotspot region while employing fundamentally different neutralization mechanisms. These findings establish structure-guided principles for the rational design of next-generation PD-L1 modulators across diverse therapeutic modalities.
Imma Capriello, T. Moreira Pereira, Gustavo Barbosa Reis et al.· Journal of Medicinal Chemist...· 0 citations
Human Chloride Intracellular Channel 1 (CLIC1) is frequently overexpressed in various tumors, where it plays a critical role in cancer cell survival by recycling vitamin C and protecting against oxidative stress. This crucial function makes targeting CLIC1's enzymatic activity a highly promising strategy for developing novel anti-cancer therapies. Despite its significant therapeutic potential, CLIC1 presents a considerable challenge in drug discovery due to its characteristically shallow, solvent-exposed active site. To overcome this hurdle, we implemented a Structure-Based Drug Design (SBDD) approach, specifically focusing on the development of covalent inhibitors. Through a rigorous process involving structure-based covalent docking and atomistic molecular dynamics simulations, we successfully identified and shortlisted several candidate covalent molecules from the NCI library that specifically target the CLIC1 active site. Subsequent in vitro enzyme inhibition assays validated the effectiveness of our approach, successfully screening and identifying three potent inhibitors. To further advance our understanding and facilitate future drug optimization, we have also successfully solved the crystal structure of the CLIC1-covalent inhibitor complex at 1.9 Å resolution, providing invaluable insights into their binding mechanisms and paving the way for further anti-cancer drug discovery.
Sibasis Sahoo, Love Panchariya, Uma Chaudhary, Arockiasamy Arulandu. Covalent Inhibition of CLIC1: A Novel Strategy for Anti-Cancer Drug Discovery [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P69.
Sibasis Sahoo, L. Panchariya, Uma Chaudhary et al.· Cancer Research· 0 citations