tetano
Editor, Senior Moderator
PLoS One
. 2024 Jan 16;19(1):e0286848.
doi: 10.1371/journal.pone.0286848. eCollection 2024. Application of in-silico drug discovery techniques to discover a novel hit for target-specific inhibition of SARS-CoV-2 Mpro's revealed allosteric binding with MAO-B receptor: A theoretical study to find a cure for post-covid neurological disorder
Magdi E A Zaki[SUP] 1 [/SUP], Sami A Al-Hussain[SUP] 1 [/SUP], Aamal A Al-Mutairi[SUP] 1 [/SUP], Abdul Samad[SUP] 2 [/SUP], Vijay H Masand[SUP] 3 [/SUP], Rahul G Ingle[SUP] 4 [/SUP], Vivek Digamber Rathod[SUP] 5 [/SUP], Nikita Maruti Gaikwad[SUP] 6 [/SUP], Summya Rashid[SUP] 7 [/SUP], Pravin N Khatale[SUP] 8 [/SUP], Pramod V Burakale[SUP] 8 [/SUP], Rahul D Jawarkar[SUP] 8 [/SUP]
Affiliations
Several studies have revealed that SARS-CoV-2 damages brain function and produces significant neurological disability. The SARS-CoV-2 coronavirus, which causes COVID-19, may infect the heart, kidneys, and brain. Recent research suggests that monoamine oxidase B (MAO-B) may be involved in metabolomics variations in delirium-prone individuals and severe SARS-CoV-2 infection. In light of this situation, we have employed a variety of computational to develop suitable QSAR model using PyDescriptor and genetic algorithm-multilinear regression (GA-MLR) models (R2 = 0.800-793, Q2LOO = 0.734-0.727, and so on) on the data set of 106 molecules whose anti-SARS-CoV-2 activity was empirically determined. QSAR models generated follow OECD standards and are predictive. QSAR model descriptors were also observed in x-ray-resolved structures. After developing a QSAR model, we did a QSAR-based virtual screening on an in-house database of 200 compounds and found a potential hit molecule. The new hit's docking score (-8.208 kcal/mol) and PIC50 (7.85 M) demonstrated a significant affinity for SARS-CoV-2's main protease. Based on post-covid neurodegenerative episodes in Alzheimer's and Parkinson's-like disorders and MAO-B's role in neurodegeneration, the initially disclosed hit for the SARS-CoV-2 main protease was repurposed against the MAO-B receptor using receptor-based molecular docking, which yielded a docking score of -12.0 kcal/mol. This shows that the compound that inhibits SARS-CoV-2's primary protease may bind allosterically to the MAO-B receptor. We then did molecular dynamic simulations and MMGBSA tests to confirm molecular docking analyses and quantify binding free energy. The drug-receptor complex was stable during the 150-ns MD simulation. The first computational effort to show in-silico inhibition of SARS-CoV-2 Mpro and allosteric interaction of novel inhibitors with MAO-B in post-covid neurodegenerative symptoms and other disorders. The current study seeks a novel compound that inhibits SAR's COV-2 Mpro and perhaps binds MAO-B allosterically. Thus, this study will enable scientists design a new SARS-CoV-2 Mpro that inhibits the MAO-B receptor to treat post-covid neurological illness.
. 2024 Jan 16;19(1):e0286848.
doi: 10.1371/journal.pone.0286848. eCollection 2024. Application of in-silico drug discovery techniques to discover a novel hit for target-specific inhibition of SARS-CoV-2 Mpro's revealed allosteric binding with MAO-B receptor: A theoretical study to find a cure for post-covid neurological disorder
Magdi E A Zaki[SUP] 1 [/SUP], Sami A Al-Hussain[SUP] 1 [/SUP], Aamal A Al-Mutairi[SUP] 1 [/SUP], Abdul Samad[SUP] 2 [/SUP], Vijay H Masand[SUP] 3 [/SUP], Rahul G Ingle[SUP] 4 [/SUP], Vivek Digamber Rathod[SUP] 5 [/SUP], Nikita Maruti Gaikwad[SUP] 6 [/SUP], Summya Rashid[SUP] 7 [/SUP], Pravin N Khatale[SUP] 8 [/SUP], Pramod V Burakale[SUP] 8 [/SUP], Rahul D Jawarkar[SUP] 8 [/SUP]
Affiliations
- PMID: 38227609
- PMCID: PMC10790994
- DOI: 10.1371/journal.pone.0286848
Several studies have revealed that SARS-CoV-2 damages brain function and produces significant neurological disability. The SARS-CoV-2 coronavirus, which causes COVID-19, may infect the heart, kidneys, and brain. Recent research suggests that monoamine oxidase B (MAO-B) may be involved in metabolomics variations in delirium-prone individuals and severe SARS-CoV-2 infection. In light of this situation, we have employed a variety of computational to develop suitable QSAR model using PyDescriptor and genetic algorithm-multilinear regression (GA-MLR) models (R2 = 0.800-793, Q2LOO = 0.734-0.727, and so on) on the data set of 106 molecules whose anti-SARS-CoV-2 activity was empirically determined. QSAR models generated follow OECD standards and are predictive. QSAR model descriptors were also observed in x-ray-resolved structures. After developing a QSAR model, we did a QSAR-based virtual screening on an in-house database of 200 compounds and found a potential hit molecule. The new hit's docking score (-8.208 kcal/mol) and PIC50 (7.85 M) demonstrated a significant affinity for SARS-CoV-2's main protease. Based on post-covid neurodegenerative episodes in Alzheimer's and Parkinson's-like disorders and MAO-B's role in neurodegeneration, the initially disclosed hit for the SARS-CoV-2 main protease was repurposed against the MAO-B receptor using receptor-based molecular docking, which yielded a docking score of -12.0 kcal/mol. This shows that the compound that inhibits SARS-CoV-2's primary protease may bind allosterically to the MAO-B receptor. We then did molecular dynamic simulations and MMGBSA tests to confirm molecular docking analyses and quantify binding free energy. The drug-receptor complex was stable during the 150-ns MD simulation. The first computational effort to show in-silico inhibition of SARS-CoV-2 Mpro and allosteric interaction of novel inhibitors with MAO-B in post-covid neurodegenerative symptoms and other disorders. The current study seeks a novel compound that inhibits SAR's COV-2 Mpro and perhaps binds MAO-B allosterically. Thus, this study will enable scientists design a new SARS-CoV-2 Mpro that inhibits the MAO-B receptor to treat post-covid neurological illness.