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.