Abstract
The discovery of new pharmaceuticals via computer modeling is one of the key challenges in modern medicine. The advent of global networks of genomic, proteomic and metabolomic endeavors is ushering in an increasing number of novel and clinically important targets for screening. Computational methods are anticipated to play a pivotal role in exploiting the structural and functional information to understand specific molecular recognition events of the target macromolecule with candidate hits leading ultimately to the design of improved leads for the target. In this review, we sketch a system independent, comprehensive physicochemical pathway for lead molecule design focusing on the emerging in silico trends and techniques. We survey strategies for the generation of candidate molecules, docking them with the target and ranking them based on binding affinities. We present a molecular level treatment for distinguishing affinity from specificity of a ligand for a given target. We also discuss the significant aspects of drug absorption, distribution, metabolism, excretion and toxicity (ADMET) and highlight improved protocols required for higher quality and throughput of in silico methods employed at early stages of discovery. We present a realization of the various stages in the pathway proposed with select examples from the literature and from our own research to demonstrate the way in which an iterative process of computer design and validation can aid in developing potent leads. The review thus summarizes recent advances and presents a viewpoint on improvements envisioned in the years to come for automated computer aided lead molecule discovery.
Keywords: Computational drug discovery, in silico drug design, binding affinity, binding specificity, ADMET
Current Pharmaceutical Design
Title: From Drug Target to Leads-Sketching A Physicochemical Pathway for Lead Molecule Design In Silico
Volume: 13 Issue: 34
Author(s): S. A. Shaikh, T. Jain, G. Sandhu, N. Latha and B. Jayaram
Affiliation:
Keywords: Computational drug discovery, in silico drug design, binding affinity, binding specificity, ADMET
Abstract: The discovery of new pharmaceuticals via computer modeling is one of the key challenges in modern medicine. The advent of global networks of genomic, proteomic and metabolomic endeavors is ushering in an increasing number of novel and clinically important targets for screening. Computational methods are anticipated to play a pivotal role in exploiting the structural and functional information to understand specific molecular recognition events of the target macromolecule with candidate hits leading ultimately to the design of improved leads for the target. In this review, we sketch a system independent, comprehensive physicochemical pathway for lead molecule design focusing on the emerging in silico trends and techniques. We survey strategies for the generation of candidate molecules, docking them with the target and ranking them based on binding affinities. We present a molecular level treatment for distinguishing affinity from specificity of a ligand for a given target. We also discuss the significant aspects of drug absorption, distribution, metabolism, excretion and toxicity (ADMET) and highlight improved protocols required for higher quality and throughput of in silico methods employed at early stages of discovery. We present a realization of the various stages in the pathway proposed with select examples from the literature and from our own research to demonstrate the way in which an iterative process of computer design and validation can aid in developing potent leads. The review thus summarizes recent advances and presents a viewpoint on improvements envisioned in the years to come for automated computer aided lead molecule discovery.
Export Options
About this article
Cite this article as:
Shaikh A. S., Jain T., Sandhu G., Latha N. and Jayaram B., From Drug Target to Leads-Sketching A Physicochemical Pathway for Lead Molecule Design In Silico, Current Pharmaceutical Design 2007; 13 (34) . https://dx.doi.org/10.2174/138161207782794220
DOI https://dx.doi.org/10.2174/138161207782794220 |
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
-
A Phosphoproteomics Approach to Identify Candidate Kinase Inhibitor Pathway Targets in Lymphoma-Like Primary Cell Lines
Current Drug Discovery Technologies Cell Cycle Regulation of G-Quadruplex DNA Structures at Telomeres
Current Pharmaceutical Design Role of Micronutrients: Boron and Molybdenum in Crops and in Human Health and Nutrition
Current Nutrition & Food Science Biological Activities of Salvia santolinifolia Boiss. A Multifunctional Medicinal Plant
Current Bioactive Compounds Regulation and Quantification of Cellular Mitochondrial Morphology and Content
Current Pharmaceutical Design Applications of Biophysical Tools to Target-Based Discovery of Novel Antibacterial Leads
Current Drug Targets Damnacanthal: A Promising Compound as a Medicinal Anthraquinone
Anti-Cancer Agents in Medicinal Chemistry Subcellular Analysis of the Platelet Proteome
Current Proteomics Development and Applications of Optical Imaging Techniques in Cancer Diagnosis: Diffuse Optical Tomography and Microendoscopy
Current Medical Imaging CA125: An Increasingly Promising Biomarker of Heart Failure
Current Pharmaceutical Design Corrosion Protection Performance via Nano-Coatings Technologies
Recent Patents on Materials Science Principles of Nanoflow Liquid Chromatography and Applications to Proteomics
Current Nanoscience Detection of Diuretic Doping by Capillary Electrophoresis and Electrochemical Technology: A Mini-Review
Current Pharmaceutical Analysis Antineoplastic Activity, Structural Modification, Synthesis and Structure-activity Relationship of Dammarane-type Ginsenosides: An Overview
Current Organic Chemistry Nanotubes at Neural and Immune Synapses
Current Medicinal Chemistry Towards Characteristics of Photodynamic Drugs Specifically Aimed at Microvascular Diseases
Mini-Reviews in Medicinal Chemistry Chronopharmaceutics: A Promising Drug Delivery Finding of the Last Two Decades
Recent Patents on Drug Delivery & Formulation Synthesis of Novel Steroid Derivatives Derived from Dehydroepiandrosterone as Potential Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Development of Doxorubicin Quantification by Reductive Amination
Current Analytical Chemistry Graphene: A Comprehensive Review
Current Drug Targets