Structure-based In Silico Screening and Redesigning of Traditional Chinese Medicine Compounds against the Protease Enzyme and Capsid Protein of HIV-1 CRF01_AE

Abstract

Human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS), which makes the body susceptible to opportunistic infections. AIDS continues to be a major public health issue, causing high morbidity and mortality worldwide. HIV-1 CRF01_AE has become the predominant strain in Southeast Asia, including the Philippines. Its protease (PR) and capsid (CA) play key roles in various stages of HIV replication, which make them promising targets for drug design. This study aims to identify the traditional Chinese medicine compounds that strongly bind to HIV-1 CRF01_AE PR and CANTD in silico and to redesign them into potential drug leads. The three-dimensional (3-D) structures of HIV-1 CRF01_AE PR and CANTD were generated via homology modeling. A total of 6,699 compounds from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database were virtually screened by molecular docking to the generated models of PR and CANTD. The docked TCMSP compounds were ranked according to their binding affinities, and the top-binding TCMSP compounds were evaluated according to compliance with Lipinski’s rules. Novel ligands with increase binding affinities were designed by linking fragments of the top-binding TCMSP compounds. The redesigned ligands were docked to the generated models and ranked according to their binding energies. They were evaluated according to Lipinski’s rules, rotatable bond count, polar surface area (PSA), and solubility. The top three redesigned ligands based on binding energy and physicochemical properties are R3a (D4226x6873) (∆G = -12.2 kcal/mol), R4a (D3223x5625) (∆G = -12.1 kcal/mol), and R6a (D4810x4974) (∆G =-11.9kcal/mol) for PR and R3b (D11100x8243_v1) (∆G =-9.2 kcal/mol), R5b (D11100x8243_v2) (∆G =-9.1 kcal/mol), and R7b (D12760x8397x8243) (∆G =-8.8 kcal/mol) for CA. All of these redesigned ligands adhere to Lipinski’s Ro5 and exhibit adequate solubility except for R4a which violates the molecular weight criterion. In comparison to many FDA-approved protease inhibitors (PIs), the three redesigned ligands for PR have better physiochemical characteristics overall. The redesigned ligands in this study are recommended as potential drug leads against HIV-1 PR and CA, which may undergo further in vitro and in vivo ADMET studies, and efficacy testing in clinical trials.