Biology subjects

Athar, M.

Publications and source records attributed to Athar, M..

4 recordsLinked to original sources

bioRxiv2021

Ex Vivo Culture Models of Hidradenitis Suppurativa for defining molecular pathogenesis and treatment efficacy of novel drugs

Hidradenitis suppurativa (HS) is a complex inflammatory and debilitating skin disease for which no effective treatment is available. This is partly because of the unavailability of suitable human or animal models with which exact pathobiology of the disease can be defined. Here, we describe the development of air-liquid (A-L) interface, liquid-liquid/liquid-submersion (L-S) and bioreactor (Bio) ex vivo skin culture models. All three ex vivo platforms were effective for culturing skin samples up to day-14, with the tissue architecture and integrity remaining intact for at least 3 days for healthy skin while for 14 days for HS skin. Up to day-3, no significant differences were observed in % early apoptotic cells among all three platforms. However, an increase was observed in late apoptotic/necrotic cells in HS skin at day-3 in A-L and Bio culture of HS skin. These cultures efficiently support the growth of various cells populations, including keratinocytes and immune cells. Profiling of the inflammatory genes using HS skin from these ex vivo cultures showed dynamic expression changes at day-3 and day-14. All of these cultures are necessary to represent the inflammatory gene status of HS skin at day-0 suggesting that not all gene clusters are identically altered in each culture method. Similarly, cytokine/chemokine profiling of the supernatant from vehicle- and drug-treated ex vivo HS cultures again showed better prediction of drug efficacy against HS. Overall, development of these three systems collectively provide a powerful tool to uncover the pathobiology of HS progression and screen various drugs against HS.

pathology↗

bioRxiv2021

Structural Differences In 3C-like protease (Mpro) From SARS-CoV and SARS-CoV-2: Molecular Insights For Drug Repurposing Against COVID-19 Revealed by Molecular Dynamics Simulations.

A recent fatal outbreak of novel coronavirus SARS-CoV-2, identified preliminary as a causative agent for series of unusual pneumonia cases in Wuhan city, China has infected more than 20 million individuals with more than 4 million mortalities. Since, the infection crossed geographical barriers, the WHO permanently named the causing disease as COVID-2019 by declaring it a pandemic situation. SARS-CoV-2 is an enveloped single-stranded RNA virus causing a wide range of pathological conditions from common cold symptoms to pneumonia and fatal severe respiratory syndrome. Genome sequencing of SARS-CoV-2 has revealed 96% identity to the bat coronavirus and 79.6% sequence identity to the previous SARS-CoV. The main protease (known as 3C-like proteinase/ Mpro) plays a vital role during the infection with the processing of replicase polyprotein thus offering an attractive target for therapeutic interventions. SARS-CoV and SARS-CoV-2 Mpro shares 97% sequence identity, with 12 variable residues but none of them present in the catalytic and substrate binding site. With the high level of sequence and structural similarity and absence of any drug/vaccine against SARS-CoV-2, drug repurposing against Mpro is an effective strategy to combat COVID-19. Here, we report a detailed comparison of SARS-CoV-2 Mpro with SARS-CoV Mpro using molecular dynamics simulations to assess the impact of 12 divergent residues on the molecular microenvironment of Mpro. A structural comparison and analysis is made on how these variable residues affects the intra-molecular interactions between key residues in the monomer and biologically active dimer form of Mpro. The present MD simulations study concluded the change in microenvironment of active-site residues at the entrance (T25, T26, M49 and Q189), near the catalytic region (F140, H163, H164, M165 and H172) and other residues in substrate binding site (V35T, N65S, K88R and N180K) due to 12 mutation incorporated in the SARS-CoV-2 Mpro. It is also evident that SARS-CoV-2 dimer is more stable and less flexible state compared to monomer which may be due to these variable residues, mainly F140, E166 and H172 which are involved in dimerization. This also warrants a need for inhibitor design considering the more stable dimer form. The mutation accumulated in SARS-CoV-2 Mpro indirectly reconfigures the key molecular networks around the active site conferring a potential change in SARS-CoV-2, thus posing a challenge in drug repurposing SARS drugs for COVID-19. The new networks and changes in microenvironment identified by our work might guide attempts needed for repurposing and identification of new Mpro inhibitors.

bioinformatics↗

bioRxiv2020

Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis

COVID-19 (Coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the pathophysiology of this deadly virus is complex and largely unknown, we employ a network biology-fueled approach and integrated multiomics data pertaining to lung epithelial cells-specific coexpression network and human interactome to generate Calu-3-specific human-SARS-CoV-2 Interactome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 target central nodes of host-viral network that participate in core functional pathways. Network centrality analyses discover 28 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host modifying responses and cytokine storm. Overall, our network centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into SARS-CoV-2 pathogenicity.

systems biology↗

bioRxiv2020

Exploring Ruthenium-based organometallic inhibitors against Plasmodium Calcium Dependent Kinase 2 (PfCDPK2): a combined ensemble docking, QM paramterization and molecular dynamics study

Recent advances in the metal-organic framework (MOF) have accelerated the discovery of novel metal-based anticancer, antibacterial and antimalarial compounds. This is substantiated by many serendipitously discovered metals (Ru, Rh, and Ir) based inhibitors that established the importance of metal inserted into the known organic scaffold. Conversely, it is possible to design novel bioactive compounds by mimicking hypervalent carbon atoms by transition metals. This process can be facilitated by computational drug discovery by treating metal center using optimized parameters that can be used for molecular docking and molecular dynamics simulations. Further, the method can be plugged with high computational power and refined algorithms to interpret chemical phenomena with atomic-level insights. In the present work, we have demonstrated an approach for parameterizing three organometallic ligands (FLL, E52, and staurosporine) using MCPB.py. In particular, we report that E52 and FLL have a better shape complimentary and affinity compared to staurosporine identified inhibitor (staurosporine) against Calcium-dependent protein kinases 2 (CDPK2). This study also revealed that a flexible approach (ensemble) outperforms for the given target with dynamic movements. The calculated MMPBSA energies for staurosporine, FLL and E52 were -66.461 {+/-} 2.192, -67.182 {+/-} 1.971 and -91.339 {+/-} 2.745 kcal/mol respectively.

biochemistry↗