In silico Repurposing of Drugs for pan-HDAC and
pan-SIRT Inhibitors: Consensus Structure-based
Virtual Screening and Pharmacophore Modeling
Investigations

AVCI, Ahmet; SARI, SUAT; Kocak Aslan, Ebru

doi:10.4274/tjps.galenos.2021.25564

In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations

Suat SARI, (Hacettepe Üniversitesi Eczacılık Fakültesi, Eczacılık Kimyası Anabilim Dalı, Ankara, Türkiye)

Ahmet AVCI, (Hacettepe Üniversitesi Eczacılık Fakültesi, Eczacılık Kimyası Anabilim Dalı, Ankara, Türkiye)

Ebru KOÇAK ASLAN (Hacettepe Üniversitesi Eczacılık Fakültesi, Eczacılık Kimyası Anabilim Dalı, Ankara, Türkiye)

Turkish Journal of Pharmaceutical Sciences

5 2

Yıl: 2021 Cilt: 18 Sayı: 6 Sayfa Aralığı: 730 - 737 Metin Dili: İngilizce DOI: 10.4274/tjps.galenos.2021.25564 İndeks Tarihi: 22-06-2022

In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations

Öz:

Objectives: Drug repurposing is a highly popular approach to find new indications for drugs, which greatly reduces time and costs for drug design and discovery. Non-selective inhibitors of histone deacetylase (HDAC) isoforms including sirtuins (SIRTs) are effective against conditions like cancer. In this study, we used molecular docking to screen Food and Drug Administration (FDA)-approved drugs to identify a number of drugs with a potential to be repurposed for pan-HDAC and pan-SIRT inhibitor activity. Materials and Methods: The library of FDA-approved drugs was optimized using MacroModel. The crystal structures of HDAC1-4, 6-8, SIRT1-3, 5, 6 were prepared before the library was docked to each structure using Glide, FRED, and AutoDock Vina/PyRx. Consensus scores were derived from the docking scores obtained from each software. Pharmacophore modeling was performed using Phase. Results: Based on the consensus scores, belinostat, bexarotene, and cianidanol emerged as top virtual pan-HDAC inhibitors whereas alosetron, cinacalcet, and indacaterol emerged as virtual pan-SIRT inhibitors. Pharmacophore hypotheses for these virtual inhibitors were also suggested through pharmacophore modeling in agreement with the molecular docking models. Conclusion: The consensus approach enabled selection of the best performing drug molecules according to different software, and good scores against isoforms (virtual pan-HDAC and pan-SIRT inhibitors). The study not only proposes potential drugs to be repurposed for HDAC and SIRTrelated diseases but also provides insights for designing potent de novo derivatives.

Anahtar Kelime:

pan-HDAC ve pan-SIRT İnhibitörleri Olarak İlaçların İn silico Olarak Yeniden Konumlandırılması: Konsensüs Yapı Tabanlı Sanal Tarama ve Farmakofor Modelleme Araştırmaları

Öz:

Amaç: İlaç yeniden konumlandırma, ilaçlar için yeni endikasyonlar bulmak için oldukça popüler bir yaklaşımdır ve ilaç tasarımı ve keşfi için zaman ve maliyetleri büyük ölçüde azaltır. Sirtuinler (SIRT) dahil olmak üzere histon deasetilaz (HDAC) izoformlarının seçici olmayan inhibitörleri, kanser gibi durumlara karşı etkilidir. Bu çalışmada, pan-HDAC ve pan-SIRT inhibitör aktivitesi için yeniden kullanım potansiyeline sahip bir dizi ilacı belirlemek üzere Gıda ve İlaç Dairesi (FDA) onaylı ilaçları taramak için moleküler docking kullanılmıştır. Gereç ve Yöntemler: FDA onaylı ilaçlar kütüphanesi MacroModel ile optimize edilmiştir. HDAC1-4, 6-8, SIRT1-3, 5, 6 yapıları hazırlanarak kütüphane her bir protein yapısına Glide, FRED ve AutoDock Vina/PyRx ile kenetlenmiştir. Konsensüs skorları her yazılımdan elde edilen kenetleme skorlarından türetilmiştir. Farmakofor modelleme Phase ile gerçekleştirilmiştir. Bulgular: Konsensüs skorlarına göre belinostat, beksaroten ve siyanidanol en iyi sanal pan-HDAC inhibitörleri, alosetron, sinakalset ve indakaterol ise en iyi sanal pan-SIRT inhibitörleri olarak öne çıkmıştır. Bu sanal inhibitörler için farmakofor hipotezleri, moleküler yerleştirme docking uyumlu olarak farmakofor modellemesi yoluyla da belirlenmiştir. Sonuç: Konsensüs yaklaşımı, farklı yazılımlara göre en iyi performans gösteren ilaç moleküllerinin seçilmesini ve izoformlara (sanal pan-HDAC ve pan-SIRT inhibitörleri) karşı iyi puanlar alınmasını sağlamıştır. Çalışma, yalnızca HDAC ve SRT ile ilgili hastalıklar için yeniden kullanılabilecek potansiyel ilaçlar önermekle kalmamış, aynı zamanda güçlü de novo türevleri tasarlamak için de yol gösterici olmuştur.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

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APA	SARI S, AVCI A, Kocak Aslan E (2021). In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. , 730 - 737. 10.4274/tjps.galenos.2021.25564
Chicago	SARI SUAT,AVCI Ahmet,Kocak Aslan Ebru In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. (2021): 730 - 737. 10.4274/tjps.galenos.2021.25564
MLA	SARI SUAT,AVCI Ahmet,Kocak Aslan Ebru In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. , 2021, ss.730 - 737. 10.4274/tjps.galenos.2021.25564
AMA	SARI S,AVCI A,Kocak Aslan E In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. . 2021; 730 - 737. 10.4274/tjps.galenos.2021.25564
Vancouver	SARI S,AVCI A,Kocak Aslan E In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. . 2021; 730 - 737. 10.4274/tjps.galenos.2021.25564
IEEE	SARI S,AVCI A,Kocak Aslan E "In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations." , ss.730 - 737, 2021. 10.4274/tjps.galenos.2021.25564
ISNAD	SARI, SUAT vd. "In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations". (2021), 730-737. https://doi.org/10.4274/tjps.galenos.2021.25564

APA	SARI S, AVCI A, Kocak Aslan E (2021). In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. Turkish Journal of Pharmaceutical Sciences, 18(6), 730 - 737. 10.4274/tjps.galenos.2021.25564
Chicago	SARI SUAT,AVCI Ahmet,Kocak Aslan Ebru In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. Turkish Journal of Pharmaceutical Sciences 18, no.6 (2021): 730 - 737. 10.4274/tjps.galenos.2021.25564
MLA	SARI SUAT,AVCI Ahmet,Kocak Aslan Ebru In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. Turkish Journal of Pharmaceutical Sciences, vol.18, no.6, 2021, ss.730 - 737. 10.4274/tjps.galenos.2021.25564
AMA	SARI S,AVCI A,Kocak Aslan E In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. Turkish Journal of Pharmaceutical Sciences. 2021; 18(6): 730 - 737. 10.4274/tjps.galenos.2021.25564
Vancouver	SARI S,AVCI A,Kocak Aslan E In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations. Turkish Journal of Pharmaceutical Sciences. 2021; 18(6): 730 - 737. 10.4274/tjps.galenos.2021.25564
IEEE	SARI S,AVCI A,Kocak Aslan E "In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations." Turkish Journal of Pharmaceutical Sciences, 18, ss.730 - 737, 2021. 10.4274/tjps.galenos.2021.25564
ISNAD	SARI, SUAT vd. "In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations". Turkish Journal of Pharmaceutical Sciences 18/6 (2021), 730-737. https://doi.org/10.4274/tjps.galenos.2021.25564