Molekulsko modeliranje interakcij BCL-2 proteinov in proteina E iz virusa SARS-CoV-2

Ločniškar, Jan (author), Podlipnik, Črtomir (mentor)

Apoptoza oz. programirana celična smrt je zelo pomemben proces v celicah. Odstranjuje odvečne celice in celice, ki so pod stresom zaradi napak v replikaciji DNK ali drugih citotoksičnih dejavnikov. Napake v regulaciji apoptoze se odražajo v različnih bolezenskih stanjih in so pogosto vzrok za nastanek tumorjev. BCL-2 proteini igrajo izjemno pomembno vlogo pri uravnavanju apoptoze. Delijo se v tri oz. štiri podskupine: anti-apoptotični proteini, pro-apoptotični proteini in BH3 proteini, ki se delijo na BH3 senzibilizatorje in BH3 aktivatorje, oboji pa imajo pro-apoptotično naravo. Skupno je v BCL-2 družini preko 20 proteinov. Zdravljenja raka z inhibicijo anti-apoptotičnih proteinov poteka s posnemanjem BH3 regije pro-apoptotičnih proteinov, postopek se imenuje BH3 posnemanje (ang. BH3 mimetics). Razvitih je že nekaj molekul, ki bolj ali manj uspešno inhibirajo anti-apoptotične proteine, prva FDA odobrena molekula pa je bila ABT-199 (zdravilo Venetoclax). Homologe BCL-2 proteinov vsebujejo tudi nekateri virusi, ki v okuženi celici posegajo v apoptotične poti. Človeški koronavirusi, najpomembnejši je zagotovo SARS-CoV-2, vsebujejo regijo z BH3 motivom na proteinu E. To je najmanjši koronavirusni protein, hkrati pa izjemno pomemben. Protein E regulira stresni odziv v celici in prepreči njeno prezgodnjo smrt po okužbi, v limfocitih pa interagira s proteinom BCL-XL in z indukcijo apoptoze zmanjšuje imunski odziv. V tem delu smo z metodami virtualnega rešetanja preučevali morebitne interakcije med BH3 regijami različnih koronavirusnih proteinov E in poiskali potencialne inhibitorje BCL-2 proteinov in proteina E virusa SARS-CoV-2. Ustvarili smo zbirko zelo različnih spojin in sidranje izvedli v programu Glide, spojine z najboljšimi rezultati pa smo prenesli v program SeeSAR, kjer smo sidranje ponovno izvedli in optimizirali posamezne ligande. Izvedli smo tudi sidranje lažno pozitivnih spojin in izdelali napovedne modele QSAR za BCL-2 proteine.

• Language: Slovenian
• Keywords: BCL-2, koronavirus, molekulsko modeliranje
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Year: 2021
• PID: 20.500.12556/RUL-128328
• COBISS.SI-ID: 72145155
• Publication date in RUL: 08.07.2021

Secondary language

• Language: English
• Title: Molecular modelling of the interactions of BCL-2 proteins and protein E from virus SARS-CoV-2

Abstract

Apoptosis or programmed cell death is a very important process in cells which gets rid of excess cells and cells that undergo cell stress because of errors in DNA replication or other cytotoxic factors. Errors in apoptosis regulation are resulted in various disease and are often the cause of tumours. BCL-2 proteins have an incredibly important role in regulation of apoptosis. They are divided into 3 or 4 groups: anti-apoptotic proteins, pro-apoptotic proteins, BH3-only sensitizer proteins and BH3-only activator proteins. There are over 20 different proteins in BCL-2 family. A cancer treatment by inhibition of anti-apoptotic proteins is carried out with BH3-mimetics of BH3 region of pro-apoptotic proteins. There are few molecules developed which more or less successfully inhibit anti-apoptotic proteins. First FDA approved molecule was ABT-263 (drug Venetoclax). Homologs of BCL-2 proteins are present in many viruses and they interact with apoptotic regulatory paths in infected cells. Human coronaviruses, the most important being SARS-CoV-2, include region with BH3 motif in protein E. This is the smallest coronaviruses’ protein but at the same time extremely important. Protein E regulates cell stress response and prevent premature death of a cell after infection. In lymphocytes it interacts with protein BCL-2 and with induction of apoptosis it reduces an immune response. In this work we used virtual screening methods to study potential interactions between BH3 regions of various coronavirus’ proteins E and search for potential inhibitors of BCL-2 proteins and protein E from SARS-CoV-2 virus. We created a library of very diverse molecules and performed molecular docking in program Glide. Molecules with best results were transferred to program SeeSAR. We redocked these ligands and optimized selected molecules. We performed a docking of false positive compounds (docking of decoys) and created QSAR models for BCL-2 proteins.

• Keywords: BCL-2, coronavirus, molecular modelling