Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel corona virus that causes corona virus disease 2019 (COVID-19). The COVID-19 rapidly spread across the nations with high mortality rate even as very little is known to contain the virus at present. In the current study, we report novel natural metabolites namely, ursolic acid, carvacrol and oleanolic acid as the potential inhibitors against main protease (Mpro) of COVID-19 by using integrated molecular modeling approaches. From a combination of molecular docking and molecular dynamic (MD) simulations, we found three ligands bound to protease during 50 ns of MD simulations. Furthermore, the molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations showed that these chemical molecules have stable and favourable energies causing strong binding with binding site of Mpro protein. All these three molecules, namely, ursolic acid, carvacrol and oleanolic acid, have passed the ADME (Absorption, Distribution, Metabolism, and Excretion) property as well as Lipinski's rule of five. The study provides a basic foundation and suggests that the three phytochemicals, viz. ursolic acid, carvacrol and oleanolic acid could serve as potential inhibitors in regulating the Mpro protein's function and controlling viral replication. Communicated by Ramaswamy H. Sarma.

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Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches.

The recent appearance of COVID-19 virus has created a global crisis due to unavailability of any vaccine or drug that can effectively and deterministically work against it. Naturally, different pos...

In silico investigation of phytoconstituents from Indian medicinal herb ' Tinospora cordifolia (giloy)' against SARS-CoV-2 (COVID-19) by molecular dynamics approach.

SWEET proteins represent one of the largest sugar transporter family in the plant kingdom and play crucial roles in plant development and stress responses. In the present study, a total of 108 TaSWEET genes distributed on all the 21 wheat chromosomes were identified using the latest whole genome sequence (as against 59 genes reported in an earlier report). These 108 genes included 14 of the 17 types reported in Arabidopsis and also included three novel types. Tandem duplications (22) and segmental duplications (5) played a significant role in the expansion of TaSWEET family. A number of cis-elements were also identified in the promoter regions of TaSWEET genes, indicating response of TaSWEET genes during development and also during biotic/abiotic stresses. The TaSWEET proteins carried 4–7 trans-membrane helices (TMHs) showing diversity in structure. Phylogenetic analysis using SWEET proteins of wheat and 8 other species gave four well-known clusters. Expression analysis involving both in silico and in planta indicated relatively higher expression of TaSWEET genes in water/heat sensitive and leaf rust resistant genotypes. The results provided insights into the functional role of TaSWEETs in biotic and abiotic stresses, which may further help in planning strategies to develop high yielding wheat varieties tolerant to environmental stresses.

Further studies on sugar transporter (SWEET) genes in wheat (Triticum aestivum L.)

RWP-RKs represent a small family of transcription factors (TFs) that are unique to plants and function particularly under conditions of nitrogen starvation. These RWP-RKs have been classified in two sub-families, NLPs (NIN-like proteins) and RKDs (RWP-RK domain proteins). NLPs regulate tissue-specific expression of genes involved in nitrogen use efficiency (NUE) and RKDs regulate expression of genes involved in gametogenesis/embryogenesis. During the present study, using in silico approach, 37 wheat RWP-RK genes were identified, which included 18 TaNLPs (2865 to 7340 bp with 4/5 exons), distributed on 15 chromosomes from 5 homoeologous groups (with two genes each on 4B,4D and 5A) and 19 TaRKDs (1064 to 5768 bp with 1 to 6 exons) distributed on 12 chromosomes from 4 homoeologous groups (except groups 1, 4 and 5); 2-3 splice variants were also available in 9 of the 37 genes. Sixteen (16) of these genes also carried 24 SSRs (simple sequence repeats), while 11 genes had targets for 13 different miRNAs. At the protein level, MD simulation analysis suggested their interaction with nitrate-ions. Significant differences were observed in the expression of only two (TaNLP1 and TaNLP2) of the nine representative genes that were used for in silico expression analysis under varying levels of N at post-anthesis stage (data for other genes was not available for in silico expression analysis). Differences in expression were also observed during qRT-PCR, when expression of four representative genes (TaNLP2, TaNLP7, TaRKD6 and TaRKD9) was examined in roots and shoots of seedlings (under different conditions of N supply) in two contrasting genotypes which differed in NUE (C306 with low NUE and HUW468 with high NUE). These four genes for qRT-PCR were selected on the basis of previous literature, level of homology and the level of expression (in silico study). In particular, the TaNLP7 gene showed significant up-regulation in the roots and shoots of HUW468 (with higher NUE) during N-starvation; this gene has already been characterized in Arabidopsis and tobacco, and is known to be involved in nitrate-signal transduction pathway.

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Genome-wide identification and characterization of gene family for RWP-RK transcription factors in wheat (Triticum aestivum L.).

The recent appearance of COVID-19 virus has created a global crisis due to unavailability of any vaccine or drug that can effectively and deterministically work against it. Naturally, different possibilities (including herbal medicines having known therapeutic significance) have been explored by the scientists. The systematic scientific study (beginning with in silico study) of herbal medicines in particular and any drug in general is now possible as the structural components (proteins) of COVID-19 are already characterized. The main protease of COVID-19 virus is $\rm{M^{pro}}$ or $\rm{3CL^{pro}}$ which is a key CoV enzyme and an attractive drug target as it plays a pivotal role in mediating viral replication and transcription. In the present study, $\rm{3CL^{pro}}$ is used to study drug:3CLpro interactions and thus to investigate whether all or any of the main chemical constituents of Tinospora cordifolia (e.g., berberine $\rm{(C_{20}H_{18}NO_{4})}$, $\beta$-sitosterol $\rm{(C_{29}H_{50}O)}$, choline $\rm{(C_{5}H_{14}NO)}$, tetrahydropalmatine $\rm{(C_{21}H_{25}NO_{4})}$ and octacosanol $\rm{(C_{28}H_{58}O))}$ can be used as an anti-viral drug against SARS-CoV-2. The in silico study performed using tools of network pharmacology, molecular docking including molecular dynamics have revealed that among all considered phytochemicals in Tinospora cordifolia, berberine can regulate $\rm{3CL^{pro}}$ protein's function due to its easy inhibition and thus can control viral replication. The selection of Tinospora cordifolia was motivated by the fact that the main constituents of it are known to be responsible for various antiviral activities and the treatment of jaundice, rheumatism, diabetes, etc.

In Silico Investigation of Phytoconstituents from Indian Medicinal Herb 'Tinospora cordifolia (Giloy)' against SARS-CoV-2 (COVID-19) by Molecular Dynamics Approach

Small heat shock protein16.3 (sHSP16.3) is a crucial protein for survival of Mycobacterium tuberculosis (MTB) in its host. Besides, this protein acts as a molecular chaperone during stress and is i...

Ursolic acid and carvacrol may be potential inhibitors of dormancy protein small heat shock protein16.3 of Mycobacterium tuberculosis.

Urease (EC 3.5.1.5) is an important member of most popular amidohydrolases superfamily that is well known for catalyzes the hydrolysis of urea into ammonia and carbon dioxide. Urease protein exclusively found in a wide range of living organisms including plant, algae, bacteria, fungi and some invertebrates. In plants, urease play an important role of recapturing the nitrogen from urea. Despite its critical interplay in plants the structural and functional aspects of urease in O. sativa are still unresolved. In the present study, a three-dimensional structure of rice urease was deduced by using homology modelling based approach. Molecular dynamics simulations were performed to gain further insight into the molecular mechanism and mode of action of urease of rice. Further, the possible binding interactions of modeled structure of urease with urea were assessed by using a geometry-based molecular docking algorithm. The study reveals the role of Ser324, Ala329 and Val385 of rice urease enzyme in binding with the substrate urea. In conclusion, this study presents a 3D model of rice urease and helps understanding the molecular basis for the mechanism of urease interaction with substrate urea at atomic level.

Naveen Sharma

Papers

Ursolic acid and carvacrol may be potential inhibitors of dormancy protein small heat shock protein16.3 of Mycobacterium tuberculosis.

Homology Modeling, Molecular Docking and Molecular Dynamics Based Functional Insights into Rice Urease Bound to Urea