TOPIC: Effectiveness of drugs being developed and tried to treat COVID-19 patients.

Introduction

In response to the COVID-19 pandemic, the White House and a coalition of leading research groups have prepared the COVID-19 Open Research Dataset (CORD-19). CORD-19 is a resource of over 29,000 scholarly articles, including over 13,000 with full text, about COVID-19, SARS-CoV-2, and related coronaviruses. This freely available dataset is provided to the global research community to apply recent advances in natural language processing and other AI techniques to generate new insights in support of the ongoing fight against this infectious disease. There is a growing urgency for these approaches because of the rapid acceleration in new coronavirus literature, making it difficult for the medical research community to keep up.

Dataset Description

The CORD-19 dataset represents the most extensive machine-readable coronavirus literature collection available for data mining to date. This allows the worldwide AI research community the opportunity to apply text and data mining approaches to find answers to questions within, and connect insights across, this content in support of the ongoing COVID-19 response efforts worldwide. There is a growing urgency for these approaches because of the rapid increase in coronavirus literature, making it difficult for the medical community to keep up.

References:
https://www.kaggle.com/allen-institute-for-ai/CORD-19-research-challenge
COVID-19 Open Research Dataset (CORD-19). 2020. Version 2020-03-13. Retrieved from https://pages.semanticscholar.org/coronavirus-research. doi:10.5281/zenodo.3715506

In this work we will make use of NLP, text mining, dataframe processing and visualization resources.

Code development for insights

First, let's import the necessary libraries.

Load and Clean Data

In this step we will load the data and perform the necessary processing.

Load Metadata

Load articles (JSON Data)

All document IDs are unique, nothing to tidy up. But there seem to be missing titles, abstracts and possibly missing bodies.

We will be working with abstracts. They provide an appropriate level of detail for the question at hand. Thus, we will drop all documents that do not have an abstract.

Pre-filter by COVID-19

In order to analyze the papers related to COVID-19, we will create specific filters.

Apply Scispacy Model

We use Scispacy's en_ner_bc5cdr_md. It provides only two NER classes: DISEASE and CHEMICAL. We are mostly interested in the latter because this class will likely carry drugs and therapeutics.

nlp = en_ner_bc5cdr_md.load()
# nlp = spacy.load('../input/scispacy-model/en_ner_bc5cdr_md-0.2.4/en_ner_bc5cdr_md/en_ner_bc5cdr_md-0.2.4')
doc = nlp(example_text)
colors = {
    'CHEMICAL': 'lightpink',
    'DISEASE': 'lightorange',
}
displacy.render(doc, style='ent', options={
    'colors': colors
})

Match relevant tokens, e.g. COVID-19, trial and usage indicators

We will now perform the necessary processing to make it possible to carry out the analyzes of interest.

Example Articles that talk about COVID-19

Example abstracts (3312, 11)
TITLE: None


publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. RADERMECKER M. -Infections virales et asthme. Rev. ft.

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TITLE: Alternativ Cefoxitin (▶ 18.2.2), Amoxicillin mit BetalaktamaseHemmer


publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. 624 17 Infektionen 17.2 Bakterielle Infektionen (Auswahl) 17.2.1 Aktinomyzetales (Strahlenpilzkrankheit) Ätiologie Actinomyces israelii wird endogen, z. B. durch kariöse Zähne, erwor ben. Tage bis Mon. nach Trauma oder Gewebspenetration entstehen chron. ei ternde, indurierende und granulomatöse Entzündungen in Kiefer, Hals, Thorax, Abdomen, Haut oder Knochen. Häufig Mischinf. Risikofaktoren: Alkoholismus, Diab., fortgeschrittene Tumoren, Kachexie. Klinik Zunächst rötlich livide, dann blaurote, erst papulopustulöse, später wulstförmige, derbe Infiltrate mit Neigung zu Abszessen, Fistelbildung und sek. Osteomyelitis sowie superinfizierten Empyemen. Diagnostik Untersuchung von Granula oder Drusen in Gramfärbung, Kultur. Therapie Da häufig spät erkannt, oft chir. Sanierung erforderlich. Vorher oder zusätzlich Ampicillin/Sulbactam 3-4 × 1,5-3 g/d i. v. (▶ 18.2.1), alternativ Clin damycin (▶ 18.2.6) oder Doxycyclin (▶ 18.2.4). 17.2.2 Anaerobier Eigenschaften Bakterien, die bei verminderter O 2 Konz. (fakultativ anaerob) oder nur in Abwesenheit von O 2 wachsen. Überwiegen zahlenmäßig in der Stand ortflora und gewinnen zunehmend als Erreger von Inf. Bedeutung, die meist en dogen (Ausnahme Clostridien) durch Störung der Mukosabarriere u. a. bei Neu tropenie, Immunsuppression (erworben, medikamentös, Tumorerkr.) oder bei Immundefekten erworben werden. Typische Erregerverteilung: obere Atemwege, GIT und Urogenitaltrakt (Bacteroides spp., Fusobacterium spp., Peptostrept., Ätiologie Durch T. vincenti zusammen mit Fusobakterien. Klinik Ulzerative Tonsillitis, häufig einseitig. Diagnostik Direktausstrich in Giemsa oder Fuchsinfärbung. 625 17.2 Bakterielle Infektionen (Auswahl) Rückfallfieber Ätiologie Durch B. recurrentis und duttonii. Übertragung durch Läuse oder Zecken. Klinik 4-12 d p. i. rasch eintretendes, schweres Krankheitsbild mit Kopf, Glie der und Rumpfschmerzen, Übelkeit, hohem Fieber, Hepatosplenomegalie, evtl. mit leichtem Ikterus. Fieberschübe sind mehrtägig, 2 bis 15tägige afebrile Zwi schenstadien. Diagnostik Direktnachweis in "dickem Tropfen" oder Blutausstrich (im Fieber anstieg). Serol. unzuverlässig. Therapie Doxycyclin 200 mg/d (▶ 18.2.4), Penicillin G 20 Mio. IE/d (▶ 18.2.1). Cave: einschleichend dosieren (HerxheimerReaktion). ! Meldepflicht: namentlich dir. oder indir. Nachweis bei akuter Inf. Borreliose (LymeKrankheit) Ätiologie Durch B. burgdorferi, die von Zecken der Gattung Ixodes (seltener auch durch andere Insekten) übertragen wird. Klinik • 1. Stadium (Frühstadium): IKZ ≤ 6 Wo. Erythema chronicum migrans an der Bissstelle (rote Papel mit zentrifugal wachsendem Erythem und zentraler Abblassung), selten Allgemeinbeschwerden mit Fieber, Kopfschmerzen, Myal gien, LkSchwellungen. 17.2.4 Bruzellen (BangKrankheit, Maltafieber) Ätiologie Übertragung der gramneg. aeroben Stäbchen durch unpasteurisierte Milch, Milchprodukte, Fleisch oder Ausscheidungen von Rindern, Schafen, Zie gen oder Schweinen. Erreger gelangen über Schleimhäute, kleine Hautläsionen und über den GIT in den Organismus. Klinik IKZ 5-21 d, danach undulierend intermittierendes (Bang-Krankheit: B. abortus) bzw. kontinuierlich oder septisch hohes (Maltafieber: B. melitensis) Fieber mit Kopfschmerzen, Schwitzen, Arthralgie, LkSchwellung, in > 50 % Splenomega lie, in 25 % Hepatomegalie, selten Endokarditis, Erregerpersistenz (klin. Rezidive).

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TITLE: Modeling the dynamics of novel coronavirus (2019-nCov) with fractional derivative


The present paper describes the mathematical modeling and dynamics of a novel corona virus (2019-nCoV). We describe the brief details of interaction among the bats and unknown hosts, then among the peoples and the infections reservoir (seafood market). The seafood marked are considered the main source of infection when the bats and the unknown hosts (may be wild animals) leaves the infection there. The purchasing of items from the seafood market by peoples have the ability to infect either asymptomatically or symptomatically. We reduced the model with the assumptions that the seafood market has enough source of infection that can be effective to infect people. We present the mathematical results of the model and then formulate a fractional model. We consider the available infection cases for January 21, 2020, till January 28, 2020 and parameterized the model. We compute the basic reproduction number for the data is R 0 % 2:4829. The fractional model is then solved numerically by presenting many graphical results, which can be helpful for the infection minimization.
Ó 2020 Faculty of Engineering, Alexandria University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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TITLE: None


publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
ABSTRACT.-Multiple sclerosis is a chronic disease that begins in late adolescence or adulthood. It is highly variable in its expression and severity. It is believed to be autoimmune in nature. The cause is unknown; both genetic and environmental factors have been implicated in the pathogenesis. MS generally presents with the acute or subacute onset of neurologic abnormalities that may wax and wane over many years. Diagnosis is generally made by means of observation of the clinical course in conjunction with a neurologic examination and laboratory tests. These tests may include magnetic resonance imaging of the head and spine, lumbar puncture, and evoked potentials. Treatment is based on general suppor& ive care, the use of corticosteroids for relapses, and symptomatic management of ongoing problems. The frequency of relapses can be reduced with interferon-13 (Betaseron). Copolymer 1 and interferon43 la are being evaluated by the U.S. Food and Drug Administration for approval for use for reduction in the frequency of relapses in relapsing-remitting MS. Treatment of chronic progression is often attempted with immunosuppressive agents such as corticosteroids, azathioprine, and cyclophosphamide. Use of other agents is being investigated.

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TITLE: None


publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Arch P~diatr 1998;5(Suppl 1):9s-13s © Elsevier, Paris l pid miologie des pneumopathies communautaires de renfant. Donn es actuelles C Marguet, N Bocquel, E Mallet Unit6 des maladies respiratoires de I'enJant, service de pddiatrie, hOpital Charles-Nicolle, centre hospitaIier et universitaire, 76031 Rouen cedex, France R~sum~ Les Etiologies des pneumopathies communautaires de l'enfant varient avec l'~ge. Les infections virales prEdominent chez le nourrisson et le virus respiratoire syncytial en est toujours le principal agent responsable. Les Etiologies bact6riennes deviennent prEdominantes entre 3 et 6 ans. L'Emergence de Streptococcus pneumoniae de sensibilit6 r6duite ~ la pfnicilline, la raise en cause de Haemophilus inlTuenzae non typables et sEcr6teur de [3-1actamase, et la place importante des germes atypiques Mycoplasma imeumoniae et Chlamydia pneumoniae sont h l'origine de nouvelles rEflexions th6rapeutiques. La mortalitE li6e aux pneumopathies reste faible dans les pays industrialisEs. Cependant, la morbidit~ semble augmenter et il est n6cessaire de s'assurer de la guErison clinique et radiologique.
pneumopathies aigu~s /enfants/nourrissons/~pid~miologie
Viruses, particularly syncitial respirator), virus, are the main aetiology of community-acquired lower respiratory tract infections in infants, while bacterial agents are more frequently responsible in children older than 3 years. Antimicrobial therapy must take into account the development of reduced susceptibility of penicillin to strains ofS~'eptoccocus pneumoniae and Haemophilus influenzae with 9-lactamase, and high frequency of Mycoplasma pneumoniae and Chlamydia pneumoniae infections. Although the mortaliO, rate has remained low in France, the morbidio, appeared to increase in recent years.
acute pneumonia / children / infants / epidemiology

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Extract all drugs and therapeutics from abstracts

Drop all chemicals that appear less than N times in the whole dataset. In the remaining, blacklist all false positives after manual inspection. Plot the remaining chemicals by occurrence frequency.

Simple Concordance Visualiser

Helps to compile the above blacklist as well as see contexts in which the above drug names appear.

Organise matches by Drugs/Therapeutics

Above, we compiled a list of drugs/therapeutics that are relevant in the context of COVID-19. Now, we can dive deeper into the contexts these drugs appear in.

To this end, we match words that indicate the context of the drug mention:

drug is in an idea stage (e.g. 'darunavir could be useful against COVID-19')
drug is in a trial stage (e.g. 'lopinavir is currently being trialled')
drug is in usage stage (e.g. 'patients are being treated with ritonavir')

These 'indicator' words are marked as additional entities in context.

Code for highlight the text

Molecular Structure

Clustering the cited compounds

In this routine we will group the top cited compounds in clusters according to their molecular structure. Here we use PCA to reduce dimensionality and create a cluster with kmeans algorithm.

We can clearly see the separation of compounds groups. The most important of which are: antiretroviral protease inhibitors, corticosteroids, polyene antibiotics, glycosaminoglycans heparan sulfate, proteases and aminoquinoline derivatives. Note: It was checked on Pubchem database.

Public References: (In case of doubt to which chemical class a certain compound belongs, you can consult the public database PubChem )
https://pubchem.ncbi.nlm.nih.gov
https://pubchem.ncbi.nlm.nih.gov/compound/392622
https://pubchem.ncbi.nlm.nih.gov/compound/5755
https://pubchem.ncbi.nlm.nih.gov/compound/213039
https://pubchem.ncbi.nlm.nih.gov/compound/70678539
https://pubchem.ncbi.nlm.nih.gov/compound/5479537
https://pubchem.ncbi.nlm.nih.gov/compound/Amphotericin%20B

Printing and comparing molecular structures

Now we will print and compare those mentioned with other drugs with similar molecular structures in the public ChEMBL database. You can find more information about the database on https://www.ebi.ac.uk/chembl/

Note: If you want to zoom in, or rotate de molecule, just click, scroll and move the mouse inside the molecule picture. Note 2: We will select only few compounds.

0            angiotensin
1                trypsin
2                     CP
3            chloroquine
4    lopinavir/ritonavir
Name: chemical_name, dtype: object

..................................................................................

Structure of angiotensin


Molecules that have at least 85% similarity with angiotensin

..................................................................................

Structure of trypsin


Sorry, structure not found in Chembl database.

..................................................................................

Structure of CP


Sorry, structure not found in Chembl database.

..................................................................................

Structure of chloroquine


Molecules that have at least 85% similarity with chloroquine

..................................................................................

Structure of lopinavir/ritonavir


Molecules that have at least 85% similarity with lopinavir/ritonavir

As a result we have a group of molecules structurally related to the researched compound.
Such a result may be useful in further research in the search for potential new drugs.

Conclusion

In this notebook we present a technique to analyse the documents provided in search of relevant information about drugs being developed.

A method was developed to find the relevant files among those provided in the challenge.

Subsequently, a routine was developed whose objective is to find the words of interest as well as highlight them in the text and evaluate the context in which they are found.

All of this allows the user to quickly and efficiently search various files of interest.

It was also evaluated the correlation of the molecular structure of the most mentioned compounds among themselves, through clustering.

Finally, the algorithm also searches the public CHEMBL database to find the chemical structure of the studied compound, as well as finding similar structures available in the database for further research by the user.

With the work it was possible to reach the following conclusions:

Several articles cite therapeutics with the use of drugs from different classes, such as antiretroviral protease inhibitors, corticosteroids, polyene antibiotics, glycosaminoglycans heparan sulfate, proteases and aminoquinoline derivatives.
There are 23 ongoing clinical trialsTRIALS in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro.(https://www.sciencedirect.com/science/article/pii/S0883944120303907?via%3Dihub)
Chloroquine was a highly effective treatment for falciparum malaria in The Gambia. High-grade resistance will soon preclude the use of chloroquine in severe malaria.(https://www.thelancet.com/journals/lancet/article/PII0140-6736(92)91645-O/fulltext)
(Chymo)trypsin-like serine fold proteases belong to the serine/cysteine proteases found in eukaryotes, prokaryotes, and viruses. For that reason, their catalytic activity is carried out using a triad of amino acids, a nucleophile, a base, and an acid. For this superfamily of proteases, they propose the existence of a universal 3D structure comprising 11 amino acids near the catalytic nucleophile and base -Nucleophile-Base Catalytic Zone (NBCZone).(https://www.sciencedirect.com/science/article/pii/S0141813019386854?via%3Dihub)
The structure models of two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteases, coronavirus endopeptidase C30 (CEP_C30) and papain like viral protease (PLVP), were built by homology modeling. Ritonavir, lopinavir and darunavir were then docked to the models, respectively, followed by energy minimization of the protease-drug complexes. In the simulations, ritonavir can bind to coronavirus endopeptidase C30 (CEP_C30) most suitably, and induce significant conformation changes of CEP_C30; lopinavir can also bind to CEP_C30 suitably, and induce significant conformation changes of CEP_C30; darunavir can bind to PLVP suitably with slight conformation changes of PLVP. It is suggested that the therapeutic effect of ritonavir and lopinavir on COVID-19 may be mainly due to their inhibitory effect on CEP_C30, while ritonavirL may have stronger efficacy ; the inhibitory effect of darunavir on SARS-CoV-2 and its potential therapeutic effect may be mainly due to its inhibitory effect on PLVP. (https://www.biorxiv.org/content/10.1101/2020.01.31.929695v2)
A total of 26 patients received intravenous administration of methylprednisolone with a dosage of 1-2mg/kg/d for 5-7 days, while the remaining patients not. The average number of days for body temperature back to the normal range was significantly shorter in patients with administration of methylprednisolone when compared to those without administration of methylprednisolone (2.06±0.28 vs. 5.29±0.70, P=0.010). The patients with administration of methylprednisolone had a faster improvement of SpO2, while patients without administration of methylprednisolone had a significantly longer interval of usingUSAGES supplemental oxygen therapy (8.2days[IQR 7.0-10.3] vs. 13.5days(IQR 10.3-16); P<0.001). In terms of chest CT, the absorption degree of the focus was significantly better in patients with administration of methylprednisolone. Our dataTRIALS indicate that in patients with severe COVID-19 pneumonia, early, lowdose and short-term application of corticosteroid was associated with a faster improvement of clinical symptoms and absorption of lung focus. (https://www.medrxiv.org/content/10.1101/2020.03.06.20032342v1)
It was studied the interaction between the SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) and heparin. The data demonstrate an interaction between the recombinant surface receptor binding domain and the polysaccharide. This has implications for the rapid development of a first-line therapeutic by repurposing heparin and for next-generation, tailor-made, GAG-based antivirals.(https://www.biorxiv.org/content/10.1101/2020.02.29.971093v1)

The results show that the technique can be used to gain important insights into the about drugs and therapeutics related to coronavirus pandemic, in an agile way and without having to read thousands of full papers.

Pros and cons

About the technique used, we can highlight the ease and speed of obtaining the required information.

As cons, we emphasize that depending on the number of files to be evaluated, the execution of the algorithm can take a while.

	cord_uid	sha	source_x	title	doi	pmcid	pubmed_id	license	abstract	publish_time	authors	journal	Microsoft Academic Paper ID	WHO #Covidence	has_full_text	full_text_file	url
0	vho70jcx	f056da9c64fbf00a4645ae326e8a4339d015d155	biorxiv	SIANN: Strain Identification by Alignment to N...	10.1101/001727	NaN	NaN	biorxiv	Next-generation sequencing is increasingly bei...	2014-01-10	Samuel Minot; Stephen D Turner; Krista L Ternu...	NaN	NaN	NaN	True	biorxiv_medrxiv	https://doi.org/10.1101/001727
1	i9tbix2v	daf32e013d325a6feb80e83d15aabc64a48fae33	biorxiv	Spatial epidemiology of networked metapopulati...	10.1101/003889	NaN	NaN	biorxiv	An emerging disease is one infectious epidemic...	2014-06-04	Lin WANG; Xiang Li	NaN	NaN	NaN	True	biorxiv_medrxiv	https://doi.org/10.1101/003889

	doc_id	title	abstract	body
0	86a998617c077f4fe2ab26214995a3548fbc0fc5	Middle East Respiratory Syndrome and Severe Ac...	The recent emergence of the Middle East respir...	While most CoVs cause the common cold in human...
1	948aaeb2e0be11ad90562bf10d462531a1f00eac	Integrated, Multi-cohort Analysis Identifies C...	Graphical Abstract Highlights d MVS is a commo...	Clinically relevant respiratory viral signatur...
2	ab680d5dbc4f51252da3473109a7885dd6b5eb6f	Evolutionary Medicine IV. Evolution and Emerge...	None	The evolutionary history of humans is characte...

	doc_id	title	abstract	body	title_has_covid19	abstract_has_covid19	title_doc	abstract_doc	abstract_trial_matches	abstract_usage_matches	abstract_idea_matches
0	acd84940fc5cd8e8f54efd04ab672f5afbd2d7df	None	publicly funded repositories, such as the WHO ...	Les infections respiratoires ~t rhinovirus, pa...	False	True	None	(publicly, funded, repositories, ,, such, as, ...	[]	[]	[]
1	e0ea1ef905ee29982a58399b858842a8e212116e	Alternativ Cefoxitin (▶ 18.2.2), Amoxicillin m...	publicly funded repositories, such as the WHO ...	Obligat intrazelluläre, zellwandlose Bakterien...	False	True	(Alternativ, Cefoxitin, (, ▶, 18.2.2, ), ,, Am...	(publicly, funded, repositories, ,, such, as, ...	[]	[]	[]
2	8605e1247b39f6fa0d909b356eb198aacd09843c	Modeling the dynamics of novel coronavirus (20...	The present paper describes the mathematical m...	One of the greatest assignments given to human...	True	True	(Modeling, the, dynamics, of, novel, coronavir...	(The, present, paper, describes, the, mathemat...	[(162, 163)]	[(94, 95)]	[(63, 64)]

	chemical_name	chemical	trials	usages	ideas
0	angiotensin	[(ff18efb2e82ebc22ce76fca5552489439cf48ef1, 19...	[(c672f5b0d7c0a40f7cc1bdf079066d72eb8f64ec, 41...	[(ff18efb2e82ebc22ce76fca5552489439cf48ef1, 18...	[(5b4707dbb9908080a2368e45298982ef80cc8c68, 38...
1	trypsin	[(6160b70c9ba139ee9e4b2accd40954bec9b46f07, 61...	[(6160b70c9ba139ee9e4b2accd40954bec9b46f07, 12...	[(6160b70c9ba139ee9e4b2accd40954bec9b46f07, 11...	[(6160b70c9ba139ee9e4b2accd40954bec9b46f07, 10...
2	CP	[(8a6d8754a8f644b6decc50b0ea53493105d21ac5, 14...	[]	[]	[]