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Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products.

ABSTRACT: Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available in the supplementary material.

SUBMITTER: Chavez-Hernandez AL

PROVIDER: S-EPMC8698858 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products.

Chávez-Hernández Ana L AL Juárez-Mercado K Eurídice KE Saldívar-González Fernanda I FI Medina-Franco José L JL

Biomolecules 20211201 12

Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is high ...[more]

PMID: 34944448

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Project description:The emergence of drug resistance against the known hookworm drugs namely albendazole and mebendazole and their reduced efficacies necessitate the need for new drugs. Chemically diverse natural products present plausible templates to augment hookworm drug discovery. The present work utilized pharmacoinformatics techniques to predict African natural compounds ZINC95486082, ZINC95486052 and euphohelionon as potential inhibitory molecules of the hookworm Necator americanus β tubulin gene. A library of 3390 compounds was screened against a homology-modelled structure of β tubulin. The docking results obtained from AutoDock Vina was validated with an acceptable area under the curve (AUC) of 0.714 computed from the receiver operating characteristic (ROC) curve. The three selected compounds had favourable binding affinities and were predicted to form no interactions with the resistance-associated mutations Phe167, Glu198 and Phe200. The compounds were predicted as anthelmintics using a Bayesian-based technique and were pharmacologically profiled to be druglike. Further molecular dynamics simulations and MM-PBSA calculations showed the compounds as promising anthelmintic drug leads. Novel critical residues comprising Leu246, Asn247 and Asn256 were also predicted for binding. Euphohelionon was selected as a template for the de novo fragment-based design of five compounds labelled A1, A2, A3, A4 and A5; with four of them having SAscore values below 6, denoting easy synthesis. All the five de novo molecules docked firmly in the binding pocket of the β tubulin with no binding interactions with the three known resistance mutation residues. Binding energies of -8.2, -7.6, -7.3, -7.2 and -6.8 kcal/mol were obtained for A1, A2, A3, A4 and A5, respectively. The identified compounds can serve as treasure troves from which future potent anthelmintics can be designed. The current study strives to assuage the hookworm disease burden, especially making available molecules with the potential to circumvent the chemoresistance.

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Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products.

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Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products.

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