Molecular Property Diagnostic Suite for COVID-19 (MPDSCOVID-19): an open-source disease-specific drug discovery portal.

Molecular Property Diagnostic Suite (MPDS) was conceived and developed as an open-source disease-specific web portal based on Galaxy. MPDSCOVID-19 was developed for COVID-19 as a one-stop solution for drug discovery research. Galaxy platforms enable the creation of customized workflows connecting various modules in the web server. The architecture of MPDSCOVID-19 effectively employs Galaxy v22.04 features, which are ported on CentOS 7.8 and Python 3.7. MPDSCOVID-19 provides significant updates and the addition of several new tools updated after six years. Tools developed by our group in Perl/Python and open-source tools are collated and integrated into MPDSCOVID-19 using XML scripts. Our MPDS suite aims to facilitate transparent and open innovation. This approach significantly helps bring inclusiveness in the community while promoting free access and participation in software development. Availability & Implementation: The MPDSCOVID-19 portal can be accessed at https://mpds.neist.res.in:8085/.

Polypharmacology guided drug repositioning approach for SARS-CoV2.

Drug repurposing has emerged as an important strategy and it has a great potential in identifying therapeutic applications for COVID-19. An extensive virtual screening of 4193 FDA approved drugs has been carried out against 24 proteins of SARS-CoV2 (NSP1-10 and NSP12-16, envelope, membrane, nucleoprotein, spike, ORF3a, ORF6, ORF7a, ORF8, and ORF9b). The drugs were classified into top 10 and bottom 10 drugs based on the docking scores followed by the distribution of their therapeutic indications. As a result, the top 10 drugs were found to have therapeutic indications for cancer, pain, neurological disorders, and viral and bacterial diseases. As drug resistance is one of the major challenges in antiviral drug discovery, polypharmacology and network pharmacology approaches were employed in the study to identify drugs interacting with multiple targets and drugs such as dihydroergotamine, ergotamine, bisdequalinium chloride, midostaurin, temoporfin, tirilazad, and venetoclax were identified among the multi-targeting drugs. Further, a pathway analysis of the genes related to the multi-targeting drugs was carried which provides insight into the mechanism of drugs and identifying targetable genes and biological pathways involved in SARS-CoV2.

In silico investigation on the mutational analysis of BRCA1-BARD1 RING domains and its effect on nucleosome recognition and ubiquitination.

The BRCA1-BARD1 complex is a crucial tumor suppressor E3 ubiquitin ligase involved in DNA double-stranded break repair. The BRCA1-BARD1 RING domains interact with UBE2D3 through the BRCA1 interface and this complex flexibly tether to the nucleosome core particle (NCP), where BRCA1 and BARD1 interacts with histone H2A and H2B of NCP. Mutations in the BRCA1-BARD1 RING domains have been linked to familial breast and ovarian cancer. Seven mutations were analyzed to understand their effect on the binding interface of protein partners and changes in conformational dynamics. Molecular dynamics simulations revealed that mutant complexes were less conformationally flexible than the wildtype complex. Protein-protein interaction profiling showed the importance of specific molecular interactions, hotspot and hub residues, and some of these were lost in the mutant complexes. Two mutations (BRCA1L51W-K65R and BARD1C53W) hindered significant interaction between protein partners and may prevent signaling for ubiquitination of histones in NCP and other cellular targets. The structural compactness and reduced significant interaction in mutant complexes may be the possible reason of preventing ubiquitination and hinder DNA repair, resulting cancer.

Molecular dynamics simulations reveal the effect of mutations in the RING domains of BRCA1-BARD1 complex and its relevance to the prognosis of breast cancer.

The N-terminal RING-RING domain of BRCA1-BARD1 is an E3 ubiquitin ligase complex that plays a critical role in tumor suppression through DNA double stranded repair mechanism. Mutations in the BRCA1-BARD1 heterodimer RING domains were found to have an association with breast and ovarian cancer by a way of hampering the E3 ubiquitin ligase activity. Herein, the molecular mechanism of interaction, conformational change due to the specific mutations on the BRCA1-BARD1 complex at atomic level has been examined by employing molecular modeling techniques. Sixteen mutations have been selected for the study. Molecular dynamics simulation results reveal that the mutant complexes have more local perturbation with a high residual fluctuation in the zinc binding sites and central helix. A few of the BRCA1 (V11A, I21V, I42V, R71G, I31M and L51W) mutants have been experimentally identified that do not impair E3 ligase activity, display an enhanced number of H-bonds and non-bonded contacts at the interacting interface as revealed by MD simulation. The mutation of BRCA1 (C61G, C64Y, C39Y and C24R) and BARD1 (C53W, C71Y and C83R) zinc binding residues displayed a smaller number of significant H-bonds, other interactions and also loss of some of the hotspot residues. Additionally, most of the mutant complexes display relatively lower electrostatic energy, H-bonding and total stabilizing energy as compared to wild-type. The current study attempts to unravel the role of BRCA1-BARD1 mutations and delineates the structural and conformational dynamics in the progression of breast cancer.Communicated by Ramaswamy H. Sarma.

Seroepidemiological and genomic investigation of SARS-CoV-2 spread in North East region of India.

PURPOSE: Seroepidemiology and genomic surveillance are valuable tools to investigate infection transmission during a pandemic. North East (NE) India is a strategically important region being the gateway connecting the country with Southeast Asia. Here, we examined the spread of SARS-CoV-2 in NE India during the first and second waves of COVID-19 using serological and whole genome sequencing approaches. METHODS: qRT-PCR analysis was performed on a selected population (n â€‹= â€‹16,295) from June 2020 to July 2021, and metadata was collected. Immunoassays were studied (n â€‹= â€‹2026) at three-time points (August 2020, February 2021, and June 2021) and in a cohort (n â€‹= â€‹35) for a year. SARS-CoV-2 whole genomes (n â€‹= â€‹914) were sequenced and analyzed with those obtained from the databases. RESULTS: Test positivity rates (TPR) in the first and second waves were 6.34% and 6.64% in Assam, respectively, and a similar pattern was observed in other NE states. Seropositivity in the three time points was 10.63%, 40.3%, and 46.33%, respectively, and neutralizing antibody prevalence was 90.91%, 52.14%, and 69.30%, respectively. Persistence of pan-IgG-N SARS-CoV-2 antibody for over a year was observed among three subjects in the cohort group. Normal variants dominated the first wave, while B.1.617.2 and AY-sublineages dominated the second wave in the region. The prevalence of the variants co-related well with high TPR and seropositivity rate in the region and identified mostly among vaccinated individuals. CONCLUSION: The COVID-19 first wave in the region witnessed low transmission with the evolution of diverse variants. Seropositivity increased during the study period with over half of the individuals carrying neutralizing antibodies against SARS-CoV-2. High infection and seroprevalence in NE India during the second wave were associated with the dominant emergence of variants of concern.

Glycoprotein attachment with host cell surface receptor ephrin B2 and B3 in mediating entry of nipah and hendra virus: a computational investigation.

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic paramyxovirus which belongs to Henipavirus family, causes severe respiratory disease, and may lead to fatal encephalitis infections in humans. NiV and HeV glycoproteins (G) bind to the highly conserved human ephrin-B2 and B3 (EFNB2 & EFNB3) cell surface proteins to mediate the viral entry. In this study, various molecular modelling approaches were employed to understand protein-protein interaction (PPI) of NiV and HeV glycoprotein (84% sequence similarity) with Human EFN (B2 and B3) to investigate the molecular mechanism of interaction at atomic level. Our computational study emphasized the PPI profile of both the viral glycoproteins with EFN (B2 and B3) in terms of non-bonded contacts, H-bonds, salt bridges, and identification of interface hotspot residues which play a critical role in the formation of complexes that mediate viral fusion and entry into the host cell. According to the reports, EFNB2 is considered to be more actively involved in the attachment with the NiV and HeV glycoprotein; interestingly the current computational study has displayed more conformational stability in HeV/NiV glycoprotein with EFNB2 complex with relatively high binding energy as compared to EFNB3. During the MD simulation, the number of H-bond formations was observed to be less in the case of EFNB3 complexes, which may be the possible reason for less conformational stability in the EFNB3 complexes. The current detailed interaction study on the PPI may put a path forward in designing peptide inhibitors to obstruct the interaction of viral glycoproteins with host proteins, thereby inhibiting viral entry. Graphical abstract: The viral attachment and fusion of Nipah and Hendra virus was explored through the interaction between viral glycoprotein and the host cell surface ephrin protein. The MD simulation results displayed more stability in Nipah and Hendra glycoprotein with EFNB2 as compared to EFNB3. The residue Glu533 in the central cavity of HeV/NiV glycoprotein protein identified as the potential hotspot in binding with the G-H loop of EFNB2. Supplementary Information: The online version contains supplementary material available at 10.1007/s12039-022-02110-9.

A Computational Study on the Interaction of NSP10 and NSP14: Unraveling the RNA Synthesis Proofreading Mechanism in SARS-CoV-2, SARS-CoV, and MERS-CoV.

The interaction of exoribonuclease (ExoN) nonstructural protein (NSP14) with NSP10 co-factors is crucial for high-fidelity proofreading activity of coronavirus replication and transcription. Proofreading function is critical for maintaining the large genomes to ensure replication proficiency; therefore, while maintaining the viral replication fitness, quick resistance has been reported to the nucleotide analogue (NA) drugs. Therefore, targeting the NSP14 and NSP10 interacting interface with small molecules or peptides could be a better strategy to obstruct replication processes of coronaviruses (CoVs). A comparative study on the binding mechanism of NSP10 with the NSP14 ExoN domain of SARS-CoV-2, SARS-CoV, MERS-CoV, and four SARS-CoV-2 NSP14mutant complexes has been carried out. Protein-protein interaction (PPI) dynamics, per-residue binding free energy (BFE) analyses, and the identification of interface hotspot residues have been studied using molecular dynamics simulations and various computational tools. The BFE of the SARS-CoV NSP14-NSP10 complex was higher when compared to novel SARS-CoV-2 and MERS. However, SARS-CoV-2 NSP14mutant systems display a higher BFE as compared to the wild type (WT) but lower than SARS-CoV and MERS. Despite the high BFE, the SARS-CoV NSP14-NSP10 complex appears to be structurally more flexible in many regions especially the catalytic site, which is not seen in SARS-CoV-2 and its mutant or MERS complexes. The significantly high residue energy contribution of key interface residues and hotspots reveals that the high binding energy between NSP14 and NSP10 may enhance the functional activity of the proofreading complex, as the NSP10-NSP14 interaction is essential in maintaining the stability of the ExoN domain for the replicative fitness of CoVs. The factors discussed for SARS-CoV-2 complexes may be responsible for NSP14 ExoN having a high replication proficiency, significantly leading to the evolution of new variants of SARS-CoV-2. The NSP14 residues V66, T69, D126, and I201and eight residues of NSP10 (L16, F19, V21, V42, M44, H80, K93, and F96) are identified as common hotspots. Overall, the interface area, hotspot locations, bonded/nonbonded contacts, and energies between NSP14 and NSP10 may pave a way in designing potential inhibitors to disrupt NSP14-NSP10 interactions of CoVs especially SARS-CoV-2.

Applying polypharmacology approach for drug repurposing for SARS-CoV2.

Exploring the new therapeutic indications of known drugs for treating COVID-19, popularly known as drug repurposing, is emerging as a pragmatic approach especially owing to the mounting pressure to control the pandemic. Targeting multiple targets with a single drug by employing drug repurposing known as the polypharmacology approach may be an optimised strategy for the development of effective therapeutics. In this study, virtual screening has been carried out on seven popular SARS-CoV-2 targets (3CLpro, PLpro, RdRp (NSP12), NSP13, NSP14, NSP15, and NSP16). A total of 4015 approved drugs were screened against these targets. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected based on the docking score, ability to interact with four or more targets and having a reasonably good number of interactions with key residues in the targets. The MD simulations and MM-PBSA studies showed reasonable stability of protein-drug complexes and sustainability of key interactions between the drugs with their respective targets throughout the course of MD simulations. The identified four drug molecules were also compared with the known drugs namely elbasvir and nafamostat. While the study has provided a detailed account of the chosen protein-drug complexes, it has explored the nature of seven important targets of SARS-CoV-2 by evaluating the protein-drug complexation process in great detail. Graphical abstract: Drug repurposing strategy against SARS-CoV2 drug targets. Computational analysis was performed to identify repurposable approved drug candidates against SARS-CoV2 using approaches such as virtual screening, molecular dynamics simulation and MM-PBSA calculations. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected as potential candidates. Supplementary Information: The online version contains supplementary material available at 10.1007/s12039-022-02046-0.

Protein-protein interaction of RdRp with its co-factor NSP8 and NSP7 to decipher the interface hotspot residues for drug targeting: A comparison between SARS-CoV-2 and SARS-CoV.

In this study we explored the molecular mechanism of RdRp (Non-Structural Protein, NSP12) interaction with its co-factors NSP7 and NSP8 which is the main toolbox for RNA replication and transcription of SARS-CoV-2 and SARS-CoV. The replication complex is a heterotetramer consists of one NSP12, one NSP7 and two NSP8. Extensive molecular dynamics (MD) simulations were applied on both the heterotetramer complexes to generate the conformations and were used to estimate the MMPBSA binding free energy (BFE) and per-residue energy decomposition of NSP12-NSP8 and NSP12-NSP7 and NSP7-NSP8 complexes. The BFE of SARS-CoV-2 heterotetramer complex with its corresponding partner protein was significantly higher as compared to SARS-CoV. Interface hotspot residues were predicted using different methods implemented in KFC (Knowledge-based FADA and Contracts), HotRegion and Robetta web servers. Per-residue energy decomposition analysis showed that the predicted interface hotspot residues contribute more energy towards the formation of complexes and most of the predicted hotspot residues are clustered together. However, there is a slight difference in the residue-wise energy contribution in the interface NSPs on heterotetramer viral replication complex of both coronaviruses. While the overall replication complex of SARS-CoV-2 was found to be slightly flexible as compared to SARS-CoV. This difference in terms of structural flexibility/stability and energetic characteristics of interface residues including hotspots at PPI interface in the viral replication complexes may be the reason of higher rate of RNA replication of SARS-CoV-2 as compared to SARS-CoV. Overall, the interaction profile at PPI interface such as, interface area, hotspot residues, nature of bonds and energies between NSPs, may provide valuable insights in designing of small molecules or peptide/peptidomimetic ligands which can fit into the PPI interface to disrupt the interaction.

Repurposing of approved drug molecules for viral infectious diseases: a molecular modelling approach.

The identification of new viral drugs has become a task of paramount significance due to the frequent occurrence of viral infections and especially during the current pandemic. Despite the recent advancements, the development of antiviral drugs has not made parallel progress. Reduction of time frame and cost of the drug development process is the major advantage of drug repurposing. Therefore, in this study, a drug repurposing strategy using molecular modelling techniques, i.e. biological activity prediction, virtual screening, and molecular dynamics simulation was employed to find promising repurposing candidates for viral infectious diseases. The biological activities of non-redundant (4171) drug molecules were predicted using PASS analysis, and 1401 drug molecules were selected which showed antiviral activities in the analysis. These drug molecules were subjected to virtual screening against the selected non-structural viral proteins. A series of filters, i.e. top 10 drug molecules based on binding affinity, mean value of binding affinity, visual inspection of protein-drug complexes, and number of H-bond between protein and drug molecules were used to narrow down the drug molecules. Molecular dynamics simulation analysis was carried out to validate the intrinsic atomic interactions and binding conformations of protein-drug complexes. The binding free energies of drug molecules were assessed by employing MMPBSA analysis. Finally, nine drug molecules were prioritized, as promising repurposing candidates with the potential to inhibit the selected non-structural viral proteins.Communicated by Ramaswamy H. Sarma.

Fate of Sc-Ion Interaction With Water: A Computational Study to Address Splitting Water Versus Solvating Sc Ion.

An exhaustive study of Sc-ion interaction with water molecules in all its possible oxidation and spin states has been carried out to delineate the relative propensity of Sc ions toward solvation and water splitting. Potential energy surface analysis of the Sc-ion reaction with water molecules, topological analysis of bonds, and the effect of sequential solvation up to 6 water molecules have been examined. Calculated values showed good agreement with the available experimental results. Close-shell systems such as singlet mono- and tricationic Sc ions prefer to split the water molecules. In contrast, the open-shell systems such as triplet mono- and doublet dicationic Sc ions prefer to get solvated than split the water molecule. Topological analysis of electron density predicted the Sc+/2+-water bond as a noncovalent bond while Sc3+-OH2, Sc2+-OH, and Sc+-H bonds as partially covalent in nature. Energy decomposition analysis revealed that Sc ion-water interactions are driven by electrostatic energy followed by polarization energy. The current study reveals that transition metal catalysis can be one of the most effective tools to employ in water splitting, by properly tuning the electrons, spin, and ligands around the catalytic center.

Structure-Based Virtual Screening of High-Affinity ATP-Competitive Inhibitors Against Human Lemur Tyrosine Kinase-3 (LMTK3) Domain: A Novel Therapeutic Target for Breast Cancer.

Human lemur tyrosine kinase-3 (LMTK3) is an oncogenic kinase known to regulate ER-α through phosphorylation and is considered to be a novel therapeutic target for breast cancer. In this work, we have studied the ATP-binding mechanism with LMTK3 domain and also carried out virtual screening on LMTK3 to identify lead compounds using Dock blaster server. The top scored compounds obtained from Dock blaster were then narrowed down further to six lead compounds (ZINC37996511, ZINC83363046, ZINC3745998, ZINC50456700, ZINC83351792 and ZINC83364581) based on high-binding affinity and non-bonding interactions with LMTK3 using Autodock 4.2 program. We found in comparison to ATP, the lead compounds bind relatively stronger to LMTK3. The relative binding free energy results from MM-PBSA/GBSA method further indicate the strong binding affinity of lead compounds over ATP to LMTK3 in the dynamic system. Further, potential of mean force (PMF) study for ATP and lead compounds with LMTK3 have been performed to explore the unbinding processes and the free energy barrier. From the PMF results, we observed that the lead compounds have higher dissociation energy barriers than the ATP. Our findings suggest that these lead compounds may compete with ATP, and could act as probable potential inhibitors for LMTK3.

Investigation of the probable homo-dimer model of the Xeroderma pigmentosum complementation group A (XPA) protein to represent the DNA-binding core.

The Xeroderma pigmentosum complementation group A (XPA) protein functions as a primary damage verifier and as a scaffold protein in nucleotide excision repair (NER) in all higher organisms. New evidence of XPA's existence as a dimer and the redefinition of its DNA-binding domain (DBD) raises new questions regarding the stability and functional position of XPA in NER. Here, we have investigated XPA's dimeric status with respect to its previously defined DBD (XPA98-219) as well as with its redefined DBD (XPA98-239). We studied the stability of XPA98-210 and XPA98-239 homo-dimer systems using all-atom molecular dynamics simulation, and we have also characterized the protein-protein interactions (PPI) of these two homo-dimeric forms of XPA. After conducting the root mean square deviation (RMSD) analyses, it was observed that the XPA98-239 homo-dimer has better stability than XPA98-210. It was also found that XPA98-239 has a larger number of hydrogen bonds, salt bridges, and hydrophobic interactions than the XPA98-210 homo-dimer. We further found that Lys, Glu, Gln, Asn, and Arg residues shared the major contribution toward the intermolecular interactions in XPA homo-dimers. The binding free energy (BFE) analysis, which used the molecular mechanics Poisson-Boltzmann method (MM-PBSA) and the generalized Born and surface area continuum solvation model (GBSA) for both XPA homo-dimers, also substantiated the positive result in favor of the stability of the XPA98-239 homo-dimer. Communicated by Ramaswamy H. Sarma.