Identification of a PD1/PD‐L1 inhibitor by structure‐based pharmacophore modelling, virtual screening, molecular docking and biological evaluation**

Abstract

PD‐1/PD‐L1 is a critical druggable target for immunotherapy against sepsis. Chemoinformatics techniques involved the structure‐based 3D pharmacophore model development followed by virtual screening of small molecule databases to identify the small molecules against PD‐L1 pathway inhibition. Raltitrexed and Safinamide act as potent repurposed drugs, and three other Specs database compounds using in silico methods. These compounds were screened based on the pharmacophore fit score and binding affinity towards the active site of the PD‐L1 protein. In silico pharmacokinetic profiling of these screened compounds was done to test their biological activity. Next, experimental validation of the best four virtually screened hits was done in vitro for its hemocompatibility and cytotoxicity. Among these, Raltitrexed, Safinamide and Specs compound (AK‐968/40642641) effectively increased the proliferation of immune cells and IFN‐γ production. These compounds can act as potent PDL‐1 inhibitors for adjuvant therapy against sepsis.

Inhibitors of Immune Checkpoints: Small Molecule- and Peptide-Based Approaches

“…The most successful outcome in this context is the development of INCB086550 (Compound 5, Figure 2) with a demonstrated reduction in tumor growth in humanized mice with CD34 + cells and elicited gene signatures associated with T cell activation, aligning with the blockade of the PD-L1/PD-1 pathway [46]. Early findings from an ongoing phase I study affirmed the blockade of PD-L1/PD-1 in peripheral blood cells, showing heightened immune activation and effective control of tumor growth, providing a basis for a further Numerous reports have validated virtual screening as a successful approach to identifying novel small molecule PD-L1/PD-1 inhibitors [53][54][55]. Importantly, the employment of computational approaches has enabled the expansion of small molecule drug discovery efforts to various immune checkpoints other than PD-1 [56][57][58].…”

A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

“…ADME and drug-likeness prediction were calculated using the QikProp module of Schrödinger. The in vitro toxicity and PD-1/PDL-1 inhibitory activity established that the drugs Raltitrexed, Safinamide, and the natural AK-968/40642641 ( Figure 9 ) could be used as PDL-1 inhibitors [ 93 ].…”

The role of PD-1 signaling in health and immune-related diseases

“…At present, numerous anti-PD-1 antibodies (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers ( 49 ) ( Table 1 ). Approved anti-PD-1 and anti-PD-L1 antibodies differ in their molecular targets, epitope binding, affinity, structure, and pharmacokinetic characteristics ( 51 ). Based on these differences, it is possible that the efficacy and safety might vary among different anti-PD-1 and anti-PD-L1 agents ( 51 ).…”

“…Approved anti-PD-1 and anti-PD-L1 antibodies differ in their molecular targets, epitope binding, affinity, structure, and pharmacokinetic characteristics ( 51 ). Based on these differences, it is possible that the efficacy and safety might vary among different anti-PD-1 and anti-PD-L1 agents ( 51 ). Currently, most immunotherapies targeting the PD-1 axis are antibody-based drugs.…”

“…Patients with sepsis, especially severe sepsis and septic shock, had obviously higher expression levels of PD-1 on CD4+ or CD8+ T cells, PD-L1 on monocytes, sPD-1, and sPD-L1 compared with patients with non-septic infections, non-infectious inflammation, and a healthy control group ( 89 ). Currently, studies regarding anti-PD-1/PD-L1 antibodies for the treatment of sepsis in animal models or in patients with sepsis have been reported ( 51 , 90 ).…”