Patents on the soles of your shoes...: Oh patents! In silico 3D-modeling for drug design

Pharmaceutical R&D includes in vitro (test-tube), in vivo (live, animal or human) testing, and fairly recently in silico (computer) 3D-modeling of molecular interactions, for the design of vaccines and drugs.

Within the context of the COVID-19 pandemic, all of the groundwork for the accelerated vaccine development, currently underway, was launched early. Indeed, it was as early as January 12, 2020, that Chinese Health authorities made public the complete sequencing of the new coronavirus (2019 n-CoV), or Wuhan virus, as it was then called, prior to being officially designated the SARS CoV-2 by the World Health Organization (CCDCP, 2020; CAS, 2020, Institut Pasteur in Shanghai, 2020). Sequenced at lightning speed, using Next Generation Sequencing (NGS) (Shang, Oct. 2020), the Chinese preemptive release of the SARS CoV-2 virus genomes, crucial to modern drug and vaccine development, included further research. Research, such as the description of the virus (a single-strand RNA virus, belonging to the Betacoraonavirus group), identification of the S-protein as critical for binding to the host cell receptor, therefore designated as the prime target of vaccine and drug treatments, and comparative data on both the suspected origin of the virus in bats, and transmission to humans, via the infected animals of the Huanan Seafood Wholesale Market, in Wuhan (Staff, CCDCP, Jan 2020; Shi, Oct. 2020).

In turn, the Chinese public release of genomic information prompted immediate and unprecedented scientific collaboration across frontiers. The collaboration to develop vaccine and drug candidates was both immediate and unprecedented, in the face of a documented emergency. Documented, because the genomic data, released from China, included supporting data on how robust the role of the viral S-protein in securing entry into human cells. An entry point where the virus could replicate, attacking the lungs and other organs of infected persons, prior to triggering massive inflammatory responses that were fatal, when they could not be prevented.

Drug or vaccine development at the genomic level relies significantly on in silico 3D modeling, in view of supporting such queries as molecular dynamics simulating receptor molecule and substance; secondary, tertiary and quaternary protein structure prediction, binding site prediction, homology modeling for analyzing previously unknown protein function, protein threading (fold recognition) in protein modeling. In sum, programs supporting simulations for comparing nucleic acids, and the search for existing drugs and their targets, that might potentially be repurposed.

One such patented in silico 3D-modeling system, used for enzyme modeling is called Catalophore,™. This system was actually used in January 2020 by Innnophore, an Austrian company, specialized in enzyme discovery, to search for already designed protease inhibitors that could also bind to the SARS CoV-2, and be repurposed as an effective antiviral treatment for COVID-19 (Gruber, C & G. Steinkellner, Jan 23, 2020; Wang, 2020).

The technology used for this purpose, embodied in the Catalophore™ enzyme modeling system, is patented in the US utility patent application US2015302142A1, titled Determining novel enzymatic functionalities using three-dimensional point clouds representing physicochemical properties of protein cavities.

Below, the January 2020 Catalophore™ modeling of the SARS CoV-2 protease point clouds, showing favored cavities where ligands could bind for inhibiting CoV-2 protease activity, thus deactivating virus replication. [Innophore, Jan 23, 2020]. In turn, the Innophore emergency response team searched their point cloud databases for proteins with similar physicochemical configurations and known protease inhibitors to see if any of them could also bind to the SARS CoV-2 protease. Lopinavir, a previously approved HIV protease inhibitor, was then identified as the best match for inhibiting the SARS CoV-2 protease (Gruber & Steinkellner, Jan 23, 2020).

With FDA authorization granted last week for emergency use of the Pfizer-BioNTech BNT162b2 vaccine, and the upcoming review, on Dec. 17th, 2020, of the Moderna mRNA-1273 vaccine, the concerted emergency response of scientists worldwide for the development of treatments and vaccines, able to halt the spread of COVID -19, offers the glimpse of a real triumph. In other words, hope exists for effective prevention of the spread of COVID-19, at the conclusion of very grim news for the year 2020, and unspeakable statistics of the human toll.

References

Chinese Academy of Sciences (CAS). https://english.cas.cn/

Chinese Center for Disease Control and Prevention (CCDCP). http://www.chinacdc.cn/en/

Chinese Center for Disease Control and Prevention (CCDCP) - COVID-19. http://www.chinacdc.cn/en/COVID19/

CCDCP - Staff (Jan, 23, 2020) Study reveals how novel coronavirus infects humans. http://www.china.org.cn/china/2020-01/23/content_75643109.htm

Chinese Center for Disease Control (Wuhan satellite). https://www.natureindex.com/institution-outputs/china/wuhan-center-for-disease-prevention-and-control/52ae6a29140ba06f3d000003

Gruber, C and G. Steinkellner (Jan. 23, 2020) Coronavirus COVID-19, formerly called Wuhan coronavirus and 2019-nCoV: What we can find out on a structural bioinformatics level. (Austria) https://innophore.com/2019-ncov/

Innophore (company website) https://innophore.com/

Institut Pasteur of Shanghai - Chinese Academy of Sciences. http://english.shanghaipasteur.cas.cn/

Karlin-Smith, S. (Jan. 29, 2020) U.S. officials praise Chinese transparency on virus — up to a point. https://www.politico.com/news/2020/01/29/officials-praise-china-transparency-virus-108926

SARS CoV-2 – Wikipedia https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2

Shang, Y. (October 2020) Next-generation sequencing in SARS CoV- 2 identification. http://www.chinacdc.cn/en/COVID19/202011/P020201119531938682677.pdf

Shi, W. (October 2020) Genetic sequencing reveals natural origin, early spread and infectomes of SARSCoV-2 in China. http://www.chinacdc.cn/en/COVID19/202011/P020201119531353047965.pdf

Wang, J. (2020) Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study - J. Chem. Inf. Model. 2020, 60, 6, 3277–3286 https://pubs.acs.org/doi/10.1021/acs.jcim.0c00179#

WHO COVID -19 Timeline (Archived). https://www.who.int/news/item/27-04-2020-who-timeline---covid-19

WHO (Jan 12, 2020) Novel Coronavirus – China. https://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en

Wuhan Institute of Virology http://english.whiov.cas.cn/