An in silico investigation on the binding site preference of PD-1 and PD-L1 for designing antibodies for targeted cancer therapy

Abdolmaleki, Sarah; Ganjalikhani Hakemi, Mazdak; Ganjalikhany, Mohamad Reza

An in silico investigation on the binding site preference of PD-1 and PD-L1 for designing antibodies for targeted cancer therapy

dc.authorid	0000-0002-4764-7616
dc.contributor.author	Abdolmaleki, Sarah
dc.contributor.author	Ganjalikhani Hakemi, Mazdak
dc.contributor.author	Ganjalikhany, Mohamad Reza
dc.date.accessioned	2024-08-29T05:58:42Z
dc.date.available	2024-08-29T05:58:42Z
dc.date.issued	2024
dc.department	İstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.department	İstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.description.abstract	Cancer control and treatment remain a significant challenge in cancer therapy and recently immune checkpoints has considered as a novel treatment strategy to develop anti-cancer drugs. Many cancer types use the immune checkpoints and its ligand, PD-1/PD-L1 pathway, to evade detection and destruction by the immune system, which is associated with altered effector function of PD-1 and PD-L1 overexpression on cancer cells to deactivate T cells. In recent years, mAbs have been employed to block immune checkpoints, therefore normalization of the anti-tumor response has enabled the scientists to develop novel biopharmaceuticals. In vivo affinity maturation of antibodies in targeted therapy has sometimes failed, and current experimental methods cannot accommodate the accurate structural details of protein-protein interactions. Therefore, determining favorable binding sites on the protein surface for modulator design of these interactions is a major challenge. In this study, we used the in silico methods to identify favorable binding sites on the PD-1 and PD-L1 and to optimize mAb variants on a large scale. At first, all the binding areas on PD-1 and PD-L1 have been identified. Then, using the RosettaDesign protocol, thousands of antibodies have been generated for 11 different regions on PD-1 and PD-L1 and then the designs with higher stability, affinity, and shape complementarity were selected. Next, molecular dynamics simulations and MM-PBSA analysis were employed to understand the dynamic, structural features of the complexes and measure the binding affinity of the final designs. Our results suggest that binding sites 1, 3 and 6 on PD-1 and binding sites 9 and 11 on PD-L1 can be regarded as the most appropriate sites for the inhibition of PD-1-PD-L1 interaction by the designed antibodies. This study provides comprehensive information regarding the potential binding epitopes on PD-1 which could be considered as hotspots for designing potential biopharmaceuticals. We also showed that mutations in the CDRs regions will rearrange the interaction pattern between the designed antibodies and targets (PD-1 and PD-L1) with improved affinity to effectively inhibit protein-protein interaction and block the immune checkpoint.
dc.description.sponsorship	Iran National Science Foundation (INSF)	en_US
dc.identifier.citation	Abdolmaleki, S., Ganjalikhani Hakemi, M. ve Ganjalikhany, M. R. (2024). An in silico investigation on the binding site preference of PD-1 and PD-L1 for designing antibodies for targeted cancer therapy. Plos One, 19(7). http://dx.doi.org/10.1371/journal.pone.0304270
dc.identifier.doi	10.1371/journal.pone.0304270
dc.identifier.issn	1932-6203
dc.identifier.issue	7
dc.identifier.pmid	39052609
dc.identifier.scopus	2-s2.0-85199611870
dc.identifier.scopusquality	Q1
dc.identifier.uri	http://dx.doi.org/10.1371/journal.pone.0304270
dc.identifier.uri	https://hdl.handle.net/20.500.12511/12793
dc.identifier.volume	19
dc.identifier.wos	001277540300027	en_US
dc.identifier.wosquality	Q1
dc.indekslendigikaynak	Web of Science
dc.indekslendigikaynak	Scopus
dc.indekslendigikaynak	PubMed
dc.institutionauthor	Ganjalikhani Hakemi, Mazdak
dc.language.iso	en
dc.relation.ec	info:eu-repo/grantAgreement/EC/FP7/99027807
dc.relation.ispartof	Plos One	en_US
dc.relation.publicationcategory	Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rights	Attribution 4.0 International	*
dc.rights	info:eu-repo/semantics/openAccess
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject	Molecular-Dynamics
dc.subject	Affinity Maturation
dc.subject	Death 1
dc.subject	Complex
dc.subject	Mutagenesis
dc.subject	Plasticity
dc.subject	Interface
dc.subject	Stability
dc.subject	System
dc.title	An in silico investigation on the binding site preference of PD-1 and PD-L1 for designing antibodies for targeted cancer therapy
dc.type	Article