Accelerated repurposing and drug development of pulmonary hypertension therapies for COVID-19 treatment using an AI-integrated biosimulation platform

Abstract

A World Health Organization-declared pandemic, COVID-19, has affected more than 4 million people worldwide with over 100,000 deaths and growing in the United States. Due to the fast-spreading and multi-targeted nature of the virus, it is clear that drugs and/or vaccines 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 (e.g. benazepril) and calcium channel blockers (CCB, e.g. amlodipine), 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 CCB and ACEI compounds to tissues implicated in COVID-19 pathogenesis.

Artificial intelligence-driven drug repurposing and structural biology for SARS-CoV-2

“…Very recently, Chakravarty et al (2021) developed an AI-integrated Bio-simulation platform for drug development and repurposing of pulmonary hypertension therapies for COVID-19. The group conducted an in-silico modeling by using AI-integrated mechanistic modeling platform BIOiSIM with known preclinical in-vitro and in-vivo datasets for accurately simulating the systemic therapy disposition and site-of-action penetration of Angiotensin-Converting Enzyme (ACE) and calcium channel blockers (CCB) compounds to tissues playing role in COVID-19 pathogenesis.…”

In Silico Simulation of the Systemic Drug Exposure Following the Topical Application of Opioid Analgesics in Patients with Cutaneous Lesions

“…BIOiSIM is a software platform comprised of semi-mechanistic models of in vivo physiology with 16 individual compartments corresponding to critical tissues and organs in the body. Ordinary differential equations (ODEs) are used to model the interactions between the different compartments in both the pharmacokinetic (PK) and pharmacodynamic (PD) contexts [ 20 , 21 ]. Model inputs include subject-specific parameters (organ volumes, blood flow rates, tissue composition, enzyme expression levels), relevant PK mechanisms (clearance, drug dissolution, permeability), among others.…”

“…Model inputs include subject-specific parameters (organ volumes, blood flow rates, tissue composition, enzyme expression levels), relevant PK mechanisms (clearance, drug dissolution, permeability), among others. The core framework of the model has been discussed in previous publications [ 20 , 21 ]. The model used for characterizing skin permeability has previously been validated for simulating systemic disposition of transdermally-applied drugs; the work here expands on the systems biology model previously described [ 11 ].…”