- What is Lipinski’s Rule of Five and why is it important to drug design?
Lipinski's rule of five is popular as the Rule of five (RO5) or Pfizer's rule of five. It is a standing rule that evaluates drug likeness in determining whether chemical compounds that have certain biological or pharmacological activities have properties that make it a probable orally active drug for human consumption. This rule is on observing that many medication drugs have lipophilic molecules (Anastas 56). This means that the rule is applicable in drug discovery when lead structures that are pharmacologically active optimized. This increases the activity and compound selectivity insuring proper maintenance of drug-like physicochemical properties as illustrated in the Lipinski's rule. All candidate drugs conforming to the rule tend to develop lower attrition rates upon various clinical trials, hence having increased chances attaining the market. While within drug discovery, molecular weight and lipophilicity are high to improve the selectivity and affinity of such drug candidates (Wermuth 90). Therefore, it is difficult to solicit drug-likeness (that is, RO5 compliance) while at hit and lead optimization.
- What is Multi-Parameter Optimisation in drug design? In addition to potency, what other attributes are necessary for a lead molecule to become a drug?
A safe, efficacious and successful drug needs to have a proper balance of active properties. This includes the potency against the intended target, appropriate metabolism, distribution, absorption, as well as elimination (ADME) properties to promote an acceptable and safe profile. Attaining such a balance during conflicting times will have the requirements of this agent embracing a major challenge for drug discovery. The approaches to simultaneous optimization of most of the factors in a design are under 'multi-parameter optimization'. In this case, the manner in which MPO is in application efficiently designs and selects compounds of high quality (Barber & Rostron 37). It also describes the scope of methods employed within drug discovery such as simple 'rules of thumb' like the Lipinski's rule. Further, the desirability functions include considerations of pareto-optimization as well as probabilistic approaches that address the uncertainty across all forms of drug discovery data based on the predictive errors and variability of experiment (Rydzewski 57). The application also explores the manner in which such methods applied towards predicting experimental data to lower attrition while improving the drug discovery process.
- Why can the primary and secondary pharmacology of a drug can give rise to toxicity and side effects?
There are a number of factors predisposing to both primary and secondary pharmacological adversity in reactions. They include dose and pharmaceutical variation regarding drug formulation. It also includes abnormalities in pharmacokinetic and pharmacodynamic frontiers as well as drug-drug interactions. A number of the drugs, such as captopril are in clinical practice at doses that subsequently show association with unacceptable toxicity frequencies. They also illustrate lower doses found to be rather safe and effective (Boldi 86). The elderly people and patients having diseases like renal failure affecting drug handling have a higher likelihood of developing type a side effects. Most of the pharmacological work focuses on the enzyme polymorphisms such as drug oxidation as well as conjugation as some of the risk factors into drug toxicity. However, this genes search affecting susceptibility requires thorough including impacts on immune responsiveness, cell repair mechanisms, and elaboration of cytokines (Moynihan & Crean 49). The investigations can in the future avail the capability of predicting the susceptibility of a person to various drug toxicity forms.
- Why would the oral bioavailability of a Biopharmaceutics Classification System (BCS) Class II drug be reduced by solid-state polymorphism whereas that of a Class III drug would be unchanged?
Biopharmaceutical classification systems classify compounds because of their permeability and solubility. The health organizations and regulatory agencies utilize such classification systems to establishing the bioavailability of the dissolution relating to the bioequivalence of the highly soluble and extensively permeable compounds (Krishna 27). On the other hand, the pharmaceutical industry takes much advantage of the BCS-based waivers in translating to routines and outcomes of significant savings. On the other hand, there are strong scientific rationales allowing BCS-based Class II drugs to more compounds in realizing even more effectiveness. However, as clear as these benefits are, there are barriers limiting application such as absence of an international regulatory harmonization process and uncertainty of the regulatory approval procedures (Gupta 36). Upon overcoming these barriers, additional applications allowed and the full benefits of BCS Class III drug applications are in place. However, the main reason for not changing to Class II drug application is the company resources compartmentalization. However, departments like the preclinical pharmacokinetics and chemistry formulation to perform as compared to the “normal” workloads in supporting drug application.
- Why is the synthetic route used in discovery of sildenafil citrate different to that used in commercial manufacture?
Synthetic chemistry is a prerequisite of the modern society. The discipline issues much consideration to valuable resources of the world and hence enables the production of commercial chemicals needed in feeding the growing population. It also facilitates the production of numerous customized materials for which the society cannot progress without. Importantly, aspects of synthetic chemistry had a hefty impact to public health in which treatments for most of the diseases is available resulting in steady increment of life expectancy (Denton & Rostron 83). Importantly this necessitates the development of various new methods aimed at selectively developing new chemical bonds that allow the generation of drug candidates that are more complex. On the other hand, a downside of sildenafil citrate in drug research rests within the immense costs involved in developing regulatory processing for new drugs (Buss & Butler 37). This is because only 15–20 years is available for commercial protection granted for recouping the initial outlay. For this reason, pharmaceutical companies constantly seek ways of accelerating this development process through the adoption of new synthetic methodologies as well as enabling technologies for purposes of profitably generating new medications for targets, both new and old.
Works Cited
Anastas,Nicholas.Molecular Design for Hazard Reduction Using Green Chemistry. New York: ProQuest, 2008. Print
Barber,Jill.,Rostron,Chris.Pharmaceutical Chemistry. New York: Oxford University Press, 2013. Print
Boldi, Armen, M. Combinatorial Synthesis of Natural Product-Based Libraries. New York: CRC Press, 2006. Print
Buss, Antony, D., Butler,Mark, S. Natural Product Chemistry for Drug Discovery. New York: Royal Society of Chemistry, 2010. Print
Denton,Philip.,Rostron,Chris.Pharmaceutics: The Science of Medicine Design. New York: Oxford University Press, 2013. Print
Gupta,Varsha.Generating Three-dimensional Structure of Polymorphic Forms of CA-II Using Homology Modeling and Molecular Dynamics. New York: ProQuest, 2008. Print
Krishna,Rajesh.Applications of Pharmacokinetic: Principles in Drug Development. New York: Springer, 2003. Print
Moynihan,Humphrey.,Crean,Abina.Physicochemical Basis of Pharmaceuticals. New York: Oxford University Press, 2009. Print
Rydzewski,Robert. Real World Drug Discovery: A Chemist's Guide to Biotech and Pharmaceutical Research. New York: Elsevier, 2010. Print
Wermuth,Camille. The Practice of Medicinal Chemistry. New York: Academic Press, 2011. Print
