Browsing by Author "Mentes, Muratcan"

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Citation - WoS: 9
Citation - Scopus: 9
Comparative Molecular Dynamics Analyses on Pik3ca Hotspot Mutations With Pi3k Alpha Specific Inhibitors and Atp
(Elsevier Sci Ltd, 2022) Mentes, Muratcan; Karakuzulu, Basak Buse; Ucar, Gonlum Bahar; Yandim, Cihangir
PI3K pathway is heavily emphasized in cancer where PIK3CA, which encodes for the p110 alpha subunit of PI3K alpha, presents itself as the second most common mutated gene. A lot of effort has been put in developing PI3K in-hibitors, opening promising avenues for the treatment of cancer. Among these, PI3K alpha specific inhibitor alpelisib was approved by FDA for breast cancer and other alpha-isoform specific inhibitors such as inavolisib and serabelisib reached clinical trials. However, the mode of action of these inhibitors on mutated PI3K alpha and how they interact with mutant structures has not been fully elucidated yet. In this study, we are revealing the calculated in-teractions and binding affinities of these inhibitors within the context of PIK3CA hotspot mutations (E542K, E545K and H1047R) by employing molecular dynamics (MD) simulations. We performed principal component analysis to understand the motions of the protein complex during our simulations and also checked the correlated motions of all amino acids. Binding affinity calculations with MM-PBSA confirmed the consistent binding of alpelisib across mutations and revealed relatively higher affinities for inavolisib towards wild-type and H1047R mutant structures in comparison to other inhibitors. On the other hand, E542K mutation significantly impaired the interaction of inavolisib and serabelisib with PI3K alpha. We also investigated the structural relationship of the natural ligand ATP with PI3K alpha, and interestingly realized a significant reduction in binding affinity for the mutants, with potentially unexpected implications on the mechanisms that render these mutations oncogenic. Moreover, correlated motions of all residues were generally higher for ATP except the H1047R mutation which exhibited a distinguishable reduction. The results presented here could be guiding for pre-clinical and clinical studies of personalized medicine where individual mutations are a strong consideration point.
Citation - WoS: 2
Citation - Scopus: 2
In Silico Drug Screen Reveals Potential Competitive Mthfr Inhibitors for Clinical Repurposing
(Taylor & Francis Inc, 2022) Keske, Nazligul; Ozay, Basak; Tukel, Ezgi Yagmur; Mentes, Muratcan; Yandim, Cihangir
MTHFR (Methylenetetrahydrofolate reductase) is a pivotal enzyme involved in one-carbon metabolism, which is critical for the proliferation of cancer cells. In line with this, published literature showed that MTHFR knockdown caused impaired growth of multiple types of cancer cells. Moreover, higher MTHFR expression levels were linked to shorter overall survival in hepatocellular carcinoma, adrenocortical carcinoma, and low-grade glioma, bringing the need to design MTHFR inhibitors as a possible treatment option. No competitive inhibitors of MTHFR have been reported as of today. This study aimed to identify potential competitive MTHFR inhibitor candidates using an in silico drug screen. A total of 30470 molecules containing biogenic compounds, FDA-approved drugs, and those in clinical trials were screened against the catalytic pocket of MTHFR in the presence and absence of cofactors. Binding energy and ADMET analysis revealed that Vilanterol (beta 2-adrenergic agonist), Selexipag (prostacyclin receptor agonist), and Ramipril Diketopiperazine (ACE inhibitor) are potential competitive inhibitors of MTHFR. Molecular dynamics analyses and MM-PBSA calculations with these compounds particularly revealed the amino acids between 285-290 for ligand binding and highlighted Vilanterol as the strongest candidate for MTHFR inhibition. Our results could guide the development of novel MTHFR inhibitor compounds, which could be inspired by the drugs brought into the spotlight here. More importantly, these potential candidates could be quhickly tested as a repurposing strategy in pre-clinical and clinical studies of the cancers mentioned above.Communicated by Ramaswamy H. Sarma