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Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity.

ABSTRACT: We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC₅₀ = 2.8 µM) and chloroquine-resistant (RKL-9; EC₅₀ = 6.7 µM) strains of Plasmodium falciparum. Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood-brain barrier integrity in mice infected with P. berghei. ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both in vitro and in vivo studies.

SUBMITTER: Uddin A

PROVIDER: S-EPMC9020225 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity.

Uddin Amad A Gupta Sonal S Mohammad Taj T Shahi Diksha D Hussain Afzal A Alajmi Mohamed F MF El-Seedi Hesham R HR Hassan Imtaiyaz I Singh Shailja S Abid Mohammad M

Frontiers in pharmacology 20220406

We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibi ...[more]

PMID: 35462917

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Project description:The latest world malaria report revealed that human deaths caused by malaria are currently on the rise and presently stood at over 627,000 per year. In addition, more than 240 million people have the infection at any given time. These figures make malaria the topmost infectious disease and reiterate the need for continuous efforts for the development of novel chemotherapies. Malaria is an infectious disease caused majorly by the protozoan intracellular parasite Plasmodium falciparum and transmitted by mosquitoes. Reports abound on the central role of falcipains (cysteine protease enzymes) in the catabolism of hemoglobin for furnishing the plasmodium cells with amino acids that they require for development and survival in the hosts. Even though falcipains (FPs) have been validated as drug target molecules for the development of new antimalarial drugs, none of its inhibitory compounds have advanced beyond the early discovery stage. Therefore, there are renewed efforts to expand the collection of falcipain inhibitors. As a result, an interesting finding reported the discovery of a quinolinyl oxamide derivative (QOD) and an indole carboxamide derivative (ICD), with each compound demonstrating good potencies against the two essential FP subtypes 2 (FP-2) and 3 (FP-3). In this study, we utilized microsecond-scale molecular dynamics simulation computational method to investigate the interactions between FP-2 and FP-3 with the quinolinyl oxamide derivative and indole carboxamide derivative. The results revealed that quinolinyl oxamide derivative and indole carboxamide derivative bound tightly at the active site of both enzymes. Interestingly, despite belonging to different chemical scaffolds, they are coordinated by almost identical amino acid residues via extensive hydrogen bond interactions in both FP-2 and FP-3. Our report provided molecular insights into the interactions between FP-2 and FP-3 with quinolinyl oxamide derivative and indole carboxamide derivative, which we hope will pave the way towards the design of more potent and druglike inhibitors of these enzymes and will pave the way for their development to new antimalarial drugs.

Project description:The widespread transmission of SARS-CoV-2 has sparked alarm worldwide. Attaining the best drugs to treat COVID-19 at the shortest possible time is one of the most critical issues in this urgent situation. Molecular docking investigation of the therapeutic potential of marketed drugs is a fast and cost-effective approach to provide a solution to this problem. The recent research efforts have led to the resolving of the 3CLpro structure as a key protease in the lifecycle of coronavirus, which could facilitate in silico evaluation of drug candidates. Herein, the similarity between the SARS-CoV-2-3CL main protease and the other SARS-CoV receptors was evaluated via multiple sequence alignment and phylogenetic tree. The reported structure of the 3CLpro was considered as a target to identify potential inhibitors for treating COVID-19 using molecular docking based virtual screening protocol. Accordingly, a database of 50 synthetic compounds with various pharmacological usage such as antiviral, anti-inflammatory, anti-human immunodeficiency viruses, antimalarial, antibacterial, anticancer, and antioxidant including approved drugs and those undergoing clinical trials, and 40 natural compounds particularly those employed in traditional Iranian medicine was constructed. The output of multiple sequence alignment analysis showed that SARS-CoV-2 main protease shares a similarity of 96% with SARS-CoV. Also, the docking results indicated that the licofelone acyl glucuronide as an anti-inflammatory drug and delta-bilirubin as an antioxidant and anti-inflammatory agent as well as kappa-carrageenan conformer, beta-D-galactopyranosyl and calycosin 7-O-glucoside as natural compounds with minimal side-effects, according to in vitro studies, are good candidates to block the enzymatic activity of SARS-CoV-2 3CLpro. Moreover, the compound 1 with the highest negative binding energy is a chemical compound that due to its favorable interactions with the 3CLpro can be identified as a representative potential drug candidate for COVID-19. Graphic abstract Supplementary Information The online version contains supplementary material available at 10.1007/s13738-021-02235-7.

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Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity.

Publications

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity.

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