Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform

Abstract

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study

“…As the model presented has only been developed for aluminum, further research will expand this methodology to other metals known to chelate FQs and disrupt pharmacokinetics such as iron and copper. These QSPR models will then be incorporated into our integrated mechanistic modeling and artificial intelligence platform, BIOiSIM, for predicting complete drug disposition [ 86 , 87 ].…”

A Systematic Review on the Contribution of Artificial Intelligence in the Development of Medicines for COVID-2019

“…Among the identified drugs were spirapril, lisinopril, and captopril (angiotensin-converting enzyme inhibitors) and lacidipine and verapamil (calcium channel blockers). For instance, spirapril ( an ACE inhibitor antihypertensive drug used to treat hypertension ; DrugBank), lisinopril ( an ACE inhibitor used to treat hypertension, heart failure, and acute myocardial infarction ; DrugBank), and captopril ( an ACE inhibitor used for the management of essential or renovascular hypertension, congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy ; DrugBank) seems to be suitable candidates as repurposing drugs against COVID-2019 [ 40 ].…”

“…Generally, the AI methodologies were scarcely described in the selected studies; the methods of the selected studies not seemed to be fully reproductible; and in vitro or clinical findings were only reported in a limited number of studies. For instance, diverse AI platforms (e.g., IDentif.AI, BenevolentAI, or BIOiSIM) were described ( Table 1 ), although few information on these platforms were provided in the selected studies [ 28 , 30 , 31 , 33 , 35 , 40 , 42 ]. As expected, machine learning approaches, AI deep learning, AI-based algorithms, molecular docking, and/or in silico methodologies were commonly reported [ 34 , 36 , 37 , 38 , 41 , 44 ], regarding they are frequently used in drug discovering.…”

“…Overall, diverse new repurposed drugs against the treatment of COVID-2019 were suggested in this systematic review through AI techniques [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], such as: valrubicin, aprepitant, dihydroergotamine, * bivalirudin, eltrombopag, eribulin, fulvestrant, idarubicin, ivermectin, ledipasvir, lifitegrast, nystatin, regorafenib, trypan blue, vitamin E, ruxolitinib, nafcillin, nabumetone, octacosanol, cinametic acid, trabectedin, lauric acid, acorbyl palmitrate, palmidrol, salmeterol, simvastatin, guaifenesin, verteporfin, metergoline, rescinnamine, leuprolide, lusutrombopag, telotristat, fostamatinib, tofacitinib, etoricoxib, ziprasidone, interferon-gamma; cyclosporine, zidovudine, methotrexate, artemisinin, glycyrrhizin acid, quinine, suramin, albuterol, ciprofloxacin, spirapril, lisinopril, and captopril. …”

“…Clearly, AI may play a central role in the discover of new associations of drugs as well as the corresponding dosages for the treatment of COVID-2019 [ 30 , 31 , 40 , 42 ].…”