Abstract
Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.
Keywords: Free energy perturbation, computer-aided drug design, cyclophilin, HIV, reverse transcriptase, protease, inhibitor
Current Pharmaceutical Design
Title: Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations
Volume: 18 Issue: 9
Author(s): Orlando Acevedo, Zandrea Ambrose, Patrick T. Flaherty, Hadega Aamer, Prashi Jain and Somisetti V. Sambasivarao
Affiliation:
Keywords: Free energy perturbation, computer-aided drug design, cyclophilin, HIV, reverse transcriptase, protease, inhibitor
Abstract: Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.
Export Options
About this article
Cite this article as:
Acevedo Orlando, Ambrose Zandrea, T. Flaherty Patrick, Aamer Hadega, Jain Prashi and V. Sambasivarao Somisetti, Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations, Current Pharmaceutical Design 2012; 18 (9) . https://dx.doi.org/10.2174/138161212799436421
DOI https://dx.doi.org/10.2174/138161212799436421 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Raloxifene and Cardiovascular Health: Its Relationship to Lipid and Glucose Metabolism, Hemostatic and Inflammation Factors and Cardiovascular Function in Postmenopausal Women
Current Pharmaceutical Design Characterizing the Relationship Between the Chemical Structures of Drugs and their Activities on Primary Cultures of Pediatric Solid Tumors
Current Medicinal Chemistry Posttranscriptional Regulation of p53 and its Targets by RNABinding Proteins
Current Molecular Medicine Moving Beyond VEGF for Anti-angiogenesis Strategies in Gynecologic Cancer
Current Pharmaceutical Design 5-Lipoxygenase and Cyclooxygenase Inhibitory Dammarane Triterpenoid 1 from Borassus flabellifer Seed Coat Inhibits Tumor Necrosis Factor-α Secretion in LPSInduced THP-1 Human Monocytes and Induces Apoptosis in MIA PaCa-2 Pancreatic Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry Novel Target Sites for Drug Screening: A Special Reference to Cancer, Rheumatoid Arthritis and Parkinson’s Disease
Current Signal Transduction Therapy Angiogenesis: A Target for Cancer Therapy
Current Pharmaceutical Design Recent Nanocarrier Approaches for Targeted Drug Delivery in Cancer Therapy
Current Molecular Pharmacology Application of Selenium Nanoparticles in Localized Drug Targeting for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Gene Expression Studies in Multiple Sclerosis
Current Genomics HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms
Mini-Reviews in Medicinal Chemistry Synthetic Optimization of Ellipticine and Antitumor Activity of Novel Hexacyclic Derivatives of Ellipticine
Current Pharmaceutical Design Insulin-Like Growth Factor-I Molecular Pathways in Osteoblasts: Potential Targets for Pharmacological Manipulation
Current Molecular Pharmacology Modulation of pRb/E2F Functions in the Regulation of Cell Cycle and in Cancer
Current Cancer Drug Targets Tumor Bone Diseases: Molecular Mechanisms and Opportunities for Novel Treatments
Current Medicinal Chemistry - Anti-Cancer Agents Editorial (Thematic Issue: New Trends in Pharmaceutical Nanotechnology)
Current Pharmaceutical Design Osteoprotegerin A Physiological and Pharmacological Inhibitor of Bone Resorption.
Current Pharmaceutical Design Estrogen Receptors as Therapeutic Targets in Breast Cancer
Current Topics in Medicinal Chemistry RGD-based Therapy: Principles of Selectivity
Current Pharmaceutical Design The Mitochondrial Thioredoxin is Required for Liver Development in Zebrafish
Current Molecular Medicine