Magdi EA Zaki, Sami A. AL-Hussain,Aamal A. Al-Mutairi, Abdul Samad,Vijay H.Masand, Rahul G. Ingle, Vivek Digambar Rathod, Nikita Maruti Gaikwad, Summya Rashid, Pravin N. Khatale, Pramod V. Burakale, Rahul D. Jawarkar
Abstract
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.
Introduction
Coronaviruses (family: Coronaviridae, order: Nidovirales, and realm: Riboviria) are single-stranded RNA viruses [1]and have been associated with a wide range of mild to severe respiratory disorders in humans. Coronaviruses did cause two major pandemic outbreaks: severe acute respiratory syndrome (SARS) in 2003 and middle-east respiratory syndrome (MERS) in 2012, caused by SARS-CoV and MERS-CoV, respectively. SARS-CoV-2, a novel coronavirus with more than 80% genomic sequence similarity to SARS-CoV, recently posed a third global pandemic, COVID-19, in 2019 [2]. Like SARS and MERS, COVID-19 begins as a respiratory illness with symptoms such as cough, dyspnea, fever, etc. However, owing to its spread to multiple organs and systems, COVID-19 has been related to additional symptoms and clinical manifestations [3], such as neurological symptoms and cerebrospinal fluid (CSF) invasion [4], particularly in children [5,6]. Reportedly, a large number of confirmed COVID-19 patients manifest a wide range of neurological symptoms [3,7–12], such as fatigue, headache, delirium, stroke [13], dizziness, syncope [14], seizure, anorexia, and insomnia [15,16], anosmia, ageusia, myoclonus, neuropathic pain, myalgias [17–19], Guillain-Barre syndrome [20]; e.g. diarrhea [21],
Materials and methods
2.1 Data collection and curation
For the present study, a curated dataset of 106 SARS-CoV Mpro inhibitors with precise experimental half-minimal inhibitory concentrations (IC50) expressed in nM units retrieved from the binding database (https://www.binding.org/bind/chemsearch, accessed on March 2, 2022) has been used to perform a QSAR evaluation [42,53]. This dataset covers an ample chemical space composed of molecules with a wide range of pharmacophoric features and a highly distinctive range of bioactivity values expressed in IC50 and spaced between 870964 and 230 nM (See S1 Table in S1 File). For easy statistical handling of the numbers, IC50 values in nanomolar units are first expressed in corresponding molar units, then converted to pIC50 using the formula pIC50 = -logIC50. The chemical structures of five of the most active and five of the least active SARS-CoV Mpro inhibitors from a given dataset are shown in Fig 2. The complete flow chart for work is displayed in Fig 3.
Results
The occupancy of numerous molecular scaffolds, viz., non-aromatic, homo- and heteroaromatic, fused rings, spiro compounds, etc., with various different functional groups and substituents and divergent values, peculiarly covered a large chemical space. In the present work, we have identified a good number of structural features. Hence, the QSAR models built are mostly based on a divided set.
Model 1 (divided set model; training set 50% and test set 50%)
Conclusions
The demonstrated feasibility of the hit compound 4 (ZINC ID: 32719065)-MAO complex formation raises the possibility that interference with brain MAO activity is responsible for increased development and faster progression of neurodegenerative illnesses in COVID-19-infected individuals. The SARS-CoV-2 Mpro inhibition booster’s pharmacophoric features such as five bonds spaced Nitrogen and Hydrogen; sp3-Carbon and aromatic Carbon; non-ring Oxy-gen and sp3-Carbon are noxious ones like HBO atoms within six from Nitrogen; exactly five bonds spaced non-ring Carbon and sp3-Oxygen atoms are interdependent and intercorrelated and thus easy to adopt to optimize existing SARS-CoV This research shed light on the pharmacophores involved in the binding interactions that inhibit both the SARS-CoV-2 Mpro and the MAO-B receptor. Interestingly, the generated QSAR models corroborated the reported X-ray crystallography findings. The QSAR-based virtual screening successfully discovered a new lead molecule with a much higher docking score for the MAO-B receptor than the SARS-CoV-2 Mpro. With a docking score of -8.20 kcal/mol and an RMSD of 2.14, compound 4 (ZINC ID: 32719065) was anchored with SARS-CoV-2 Mpro via hydro-gen bonding contacts with the S1 and S2 pocket residues and attained similar conformation to that of the MAO-B pdb-2v61 ligand, with a docking score of -12.33 kcal/mol and an RMSD of 1.88. compound 4 (ZINC ID: 32719065), on the other hand, formed four hydrogen bonds with the water molecules and four conventional hydrogen bonding contacts with the MAO-B receptor.
Acknowledgments
We are thankful to the Deanship of Scientific Research, Imam Mohammad Ibn Saud Islamic University (IMSIU), Saudi Arabia.
Citation: Zaki MEA, AL-Hussain SA, Al-Mutairi AA, Samad A, Masand VH, Ingle RG, et al. (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. PLoS ONE 19(1): e0286848. https://doi.org/10.1371/journal.pone.0286848
Editor: Arabinda Ghosh, Gauhati University, INDIA
Received: March 22, 2023; Accepted: May 24, 2023; Published: January 16, 2024
Copyright: © 2024 Zaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This research was supported by the Deanship of Scientific Research, Imam Mohammad Ibn Saud Islamic University (IMSIU), Saudi Arabia, Grant No. (21-13-18-067)
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: SARS-CoV-2 Mpro, Main Protease; MAO-B, Monoamino oxidase B; QSAR, Quantitative structure activity Relationship; MD, Molecular Dynamic; MMGBSA, Molecular mechanics generalized born surface area; CADD, Computer Aided Drug Designing; SMILES, Simplified Molecular-Input Line-Entry System; GA, Genetic Algorithm; MLR, Multiple Linear Regression; QSAR, Quantitative Structure-Activity Relationship; OLS, Ordinary Least Square; QSARINS, QSAR Insubria; OECD, Organization for Economic Co-operation and Development; CCC, Concordance Correlation Coefficient
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0286848#ack
